Diagnosis and Management of Osteomyelitis https commons wikimedia

Diagnosis and Management of Osteomyelitis https: //commons. wikimedia. org/wiki/File: Osteomyelitis_of_the_1 st_MTP. jpg Clayton Foster, MD Owner, Airborne Infectious Disease January 7, 2020

Disclosures • No relevant financial disclosures • I will be discussing off‐label and investigational therapies

Objectives • Outline the epidemiology and classification of adult osteomyelitis • Recognize clinical manifestations of adult osteomyelitis • Apply evidence‐based treatment strategies in the management of adult osteomyelitis • Review orthopedic infections involving hardware and describe how this affects management

History • Chronic osteomyelitis was first described by Hippocrates (460‐ 370 BC) among patients with open fractures 1 • Acute hematogenous osteomyelitis was not characterized until 1773 (“abscessus in medulla”)2 • The term “osteomyelitis” was first introduced in 18443 • Early treatment was all surgical – debridement of diseased bone and packing of the remaining cavity 4

History • In the pre‐antibiotic era, mortality from osteomyelitis was estimated to be 33% 5 • Cause of death was typically either hematogenous dissemination of infection (acute OM) or secondary amyloidosis (chronic OM)6 • Almost immediately after the introduction of penicillin in 1940, mortality from osteomyelitis dropped to 10% or less 5 • After 1950, incidence and severity of osteomyelitis cases started increasing again with the rise of penicillin‐resistant Staphylococcus aureus 7 • The modern treatment approach of prolonged antibiotics with or without surgery, depending on the clinical context, was first outlined in the early 1970 s 8, 9

Current Understanding of Osteomyelitis • Classified by duration and route of infection: 10 • • Acute OM – symptoms for days to weeks Chronic OM – symptoms for months to years “Subacute” OM only exists in medical coding (M 86. 2 XX) Key difference between acute and chronic OM is development of sequestrum (dead bone) • Hematogenous • Nonhematogenous

Epidemiology • Etiology 11 • • Trauma (open fractures, pressure ulcers, penetrating injuries) Contiguous spread from infected joints or hardware Surgery Bacteremia • Risk Factors • Diabetes • Vascular disease • Peripheral neuropathy

Microbiology • We will focus on typical bacterial OM, though it can be caused by mycobacteria, fungi and even viruses (smallpox) • The most common pathogens are Staphylococcus aureus, coagulase‐negative staphylococci and aerobic Gram‐negative rods 12 • Staph species account for >50% of nonhematogenous OM • GNRs make up ~20% • Other pathogens include streptococci (12%), enterococci (8%) and anaerobes (5%) • Hematogenous OM is most often caused by Staph aureus, with aerobic GNRs causing an estimated 30% of cases 13 • Hematogenous OM is usually monomicrobial

Diagnosis • Positive bone culture is considered the gold standard (for organisms that fit the clinical picture) • Bone biopsy for pathology can make the diagnosis even with a negative culture • However, a negative biopsy does not rule out osteomyelitis 14 • MRI is the most sensitive imaging modality for detecting OM • CT may miss acute OM because it primarily picks up bony erosion • For patients who cannot get CT or MRI (or whose hardware precludes quality images), nuclear studies (3‐phase bone scan, PET/CT) have good sensitivity • Plain radiographs are least sensitive and only pick up advanced changes of OM (erosion, cortical disruption), which can be seen with other diseases

Diagnosis • You don’t need any of the previous tests to make a diagnosis of OM • Exposed bone = infected bone • The “probe‐to‐bone” test has high sensitivity and specificity for OM in meta‐analysis 15 • The presence of a sinus tract is pathognomonic of chronic OM 16 • Always suspect OM in non‐healing wounds, even in the absence of exposed bone • In studies of diabetic foot infections, OM often developed before exposed bone was present on exam 17 • Per the above study, “the majority of diabetic foot ulcers have an underlying osteomyelitis that is clinically unsuspected. ” • Ulcers larger than 2 cm 2 in diabetic foot wounds predicted OM as well at the probe‐to‐bone test in one study 18 • These rules apply to hardware infections as well

Diagnosis • You cannot rely on typical findings of infection to make (or exclude) a diagnosis of OM • A majority of patients with OM do not have fever (70% in one study)19 • A majority of patients with OM do not have leukocytosis (65% in one study) 20 • Local symptoms of redness, warmth, swelling and pain are not always present 21 • No pus ≠ no infection • Drainage from a focus of OM may be serous, serosanguinous, bloody or purulent 22 • ESR and CRP are usually elevated, but not always – especially with chronic OM 23 • Procalcitonin is not a reliable marker for OM 24

Diagnosis • Examples of when to be suspicious of OM: • A patient appears to be healing well after orthopedic surgery, but 3 weeks later, the incision dehisces and starts to drain • A venous stasis ulcer over the lateral malleolus has not healed after several months of going to wound clinic • An ischial pressure ulcer heals after intensive outpatient treatment, then breaks down dramatically as soon as the patient is released • Non‐union in the setting of orthopedic hardware • “The hardware is always infected!” (until proven otherwise)

Treatment • If at all possible, remove hardware and necrotic bone • Even without these complicating factors, I often advocate for surgical debridement to get deep cultures – surface cultures do not correlate well with bone cultures 25 • If there is any concern for residual infection following surgery (or if there is no surgery), the patient needs a minimum of 4 weeks of appropriate antibiotics 26 • My opinion: most osteomyelitis is undertreated in terms of antibiotic duration • My approach: treat to normalization of CRP and wound closure (if feasible) • Inadequately debrided chronic OM can often be cured by antibiotics alone, but it may require courses ranging from 3 months to over a year 27, 28, 29

Treatment • For patients who initially present without sepsis or overt wound infection, hold off on antibiotics until cultures can be obtained • The “antibiotic holiday” is common practice, although I personally disagree in many cases • A Cochrane review found no difference in outcomes between IV and oral antibiotic therapy in treating chronic OM 30 • However, it is still common practice to treat OM with Gram positive organisms (Staph, Strep, Enterococcus) with IV antibiotics, at least for the first few weeks • Antibiotic selection should try to account for differences in oral absorption and bone penetration

Antibiotic selection • According to a recent review, essentially all of the common IV antibiotics used to treat osteomyelitis should provide adequate bone penetration (tissue concentration >> MIC) 31 • Best bets for oral antibiotics (high oral bioavailability plus good bone penetration): • • • Fluoroquinolones Tetracyclines Clindamycin Bactrim Linezolid Metronidazole (although the review above found that bone concentration did not reliably exceed typical MICs) • Agents with notably poor bone penetration include penicillin (G/V), macrolides, imipenem and flucloxacillin (not available in the US)

Antibiotic selection • What if I don’t have a positive culture, but I’m pretty sure they have OM? • Strategy: cover all Staph and Strep species plus common Gram negatives • Common/reasonable regimens: • IV vancomycin (OFF‐LABEL) plus IV ceftriaxone 2 gm daily • IV vancomycin plus high‐dose PO Cipro (750 mg PO BID or renally‐dosed equivalent) • IV daptomycin in place of vancomycin in one of the regimens above (OFF‐LABEL) • PO linezolid or doxycycline for Gram positive coverage (both OFF‐LABEL) PLUS • High‐dose PO Cipro or Augmentin 875 mg PO BID (OFF‐LABEL) for Gram negative coverage • Probably don’t need to cover empirically for anaerobes • Look back at old cultures

Adjunctive treatments • Rifampin is the best‐studied adjunctive treatment for staphylococcal hardware infections (primarily Staph aureus, technically OFF‐LABEL) • For select cases of Staph aureus prosthetic joint infection (PJI) where the prosthesis is debrided and retained, the addition of rifampin to primary therapy can increase eradication rates from 50‐ 60% to almost 90%32‐ 36 • Data supporting use in PJI with Co. NS and Strep species are limited 37 • Rifampin is a messy drug – interacts with everything (induces multiple CYP 450 enzymes); can cause hypersensitivity reaction, hepatitis and severe dermatologic changes (SJS/TEN) • Make sure your isolate actually tests susceptible to rifampin • Do not use rifampin as monotherapy!

Adjunctive treatments • Hyperbaric oxygen (HBO) therapy is often employed to treat non‐healing wounds, but data are mostly limited to small series • A systematic review of HBO in 2009 concluded that it 38 • Reduces the chance of amputation from infected diabetic foot ulcers requiring surgery (OR 0. 24, high level of evidence) • Improves chances of healing an infected diabetic foot ulcer (OR 9. 99, high level of evidence) • Contributes to remission in about 85% of cases of refractory lower extremity OM (moderate level of evidence) • Efficacy tends to correlate with documenting hyperoxygenation of at‐risk tissue by transcutaneous oximetry

Adjunctive treatments • Local antibiotic delivery is frequently employed for OM and PJI – usually polymethylmethacrylate (PMMA) cement impregnated with antibiotics +/‐ antifungals • PMMA can be formed into beads, molded into a bony defect or used to coat hardware • Vancomycin and aminoglycosides are the most commonly used antibiotics for local delivery 39. Antifungal coverage, if added, is typically achieved with amphotericin (all OFF‐ LABEL) • Mixed results have been observed in small series using local antibiotic delivery 40‐ 43 • A number of issues have arisen in implementing this strategy

Adjunctive treatments • Problems with local antibiotic delivery: • No standardization for the type and amount of antimicrobials added • Little standardization in how cement is prepared • Elution of antibiotics is not consistent – most commonly, there is an early burst of drug into surrounding tissues, followed by a prolonged period of subtherapeutic concentrations 44 • Effects of varying the type and quantity of antimicrobials on cement strength and elution properties are not well‐described • Systemic toxicity has been reported – usually nephrotoxicity 45‐ 49 • Prolonged exposure to low‐level antibiotic concentrations can lead to bacterial resistance • Non‐absorbable media that are no longer eluting antibiotic provide surfaces for biofilm formation 50

How does hardware affect treatment? • Most principles are the same as OM without hardware, except that the minimum initial treatment period increases to 6 weeks, and suppression is needed for retained hardware • The big problem is the formation of biofilm – bacteria adhere to prosthetic material and secrete exopolysaccharides, forming a “slime layer” over the hardware 51 • Immune cells and many antibiotics have difficulty penetrating biofilm, and many organisms within the biofilm layer go dormant, making them resistant to antibiotic killing 51‐ 52

How does hardware affect treatment? • At this time, our only reliable method of removing biofilm is to remove the hardware that allowed it to form • The idea behind prolonged antibiotics is to “wait out” the dormant bacteria in the biofilm • The current standard is at least 3 months of oral suppression following the initial (usually parenteral) antibiotic course 53. With non‐union, continue until the fracture heals. • Beyond that, duration is individualized based on • • Likelihood of recurrence Potential consequences of recurrence Tolerance of suppressive antibiotics Patient preference • We have no way of knowing if/when hardware is completely sterilized. Some experts think maybe it never is 54

Surgical options for hardware infection • For fixation hardware, allow the underlying bone to heal, then remove hardware in its entirety • Prosthetic joint infections have more options: • Debridement and retention of prosthesis • One‐stage exchange arthroplasty (not really done in the US) • Two‐stage exchange arthroplasty – replace the prosthesis with a temporary spacer, treat with antibiotics until you’re convinced infection is gone, then put in a new prosthesis • Permanent resection arthroplasty – Girdlestone for hips, arthrodesis for knees • Amputation

When to worry • Wound(s) over the infection site won’t heal • Associated fractures won’t heal • A draining sinus forms and won’t close • Persistent, or especially worsening local erythema, swelling and pain • CRP won’t normalize or, worse, starts increasing • Baseline ESR increases with age more so than CRP, so it often doesn’t normalize 55

I’m worried…what now? • When OM and hardware infections do not resolve with initial therapy, the problem is almost always one of three things: • Source control (hardware or necrotic bone needs to come out) • Inadequate antibiotic coverage (the organism has become resistant or, more often, a new organism has been introduced through the open wound) • Vascular insufficiency (the affected tissues aren’t getting enough antibiotics and immune cells delivered) • My bias: I don’t care how much prednisone they take, how poorly‐controlled their diabetes is or how non‐compliant they are with their dressings – if you address all the factors above, you will eventually heal the wound

What if I can’t control the source? • Examples: chronic osteomyelitis of the skull, extensive prosthesis, unacceptable surgical risk • Pick an oral antibiotic that • Is confirmed to have activity against the organism(s) involved • Has good bone penetration • The patient can tolerate long‐term • …And don’t stop • If you don’t think you have any oral options, call your ID consultant

Prognosis • For chronic osteomyelitis without hardware, reported success rates range from 60% to 90% 56 • Hardware outcomes are even harder to predict because they depend on the organism, type and extent of hardware, duration of infection and surgical approach (debridement and retention or explant) • Reported success rates with hardware infection range from 32% with debridement, antibiotics and implant retention (DAIR) in RA patients up to 90% in one study of DAIR in Staph aureus PJI with adjunctive rifampin 32, 57 • The largest and longest study of Staph aureus PJI treated with DAIR (345 patients over 8 years) reported a long‐term success rate of only 55%32 • Two‐stage arthroplasty is estimated to eradicate infection in >85% of patients 36, 58, 59

What’s on the horizon? • Oritavancin and dalbavancin – super long‐acting injectable lipoglycopeptides (OFF‐LABEL) • Half‐lives of 245 and 346 hours, respectively • Three simultaneous mechanisms of action – development of clinically significant resistance has not been observed • Activity against stationary (dormant) phase bacteria (oritavancin > dalbavancin) 60, 61 • Ability to penetrate biofilms 60, 62 • Growing body of evidence to support efficacy in osteomyelitis 63‐ 66 • Fusidic acid (investigational) • • • Oral protein synthesis inhibitor with a unique target (elongation factor G) Limited data show efficacy against difficult‐to‐treat MRSA infections when combined with rifampin 67 Most data on treating OM are in Staph aureus, in children and with combination therapy Low barrier to resistance Not available in the US

What’s on the horizon? • Organic acids for biofilm • Acetic acid and citric acid have been used to help clear biofilm in other contexts, including • Bladder irrigation to prevent CAUTI 68 • Lock flushes to prevent infection of long‐term vascular catheters 69 • Topical application in the setting of burns 70 • We are starting to see data in PJI suggesting a significant reduction in biofilm in vitro after a 20 ‐minute soak in 3‐ 5% acetic acid 71, 72 • Phototherapy • Blue light (405 nm) appears to kill a number of clinically significant pathogens within biofilm 73 • Effective application times range from 15 to 60 minutes • This wavelength does not appear to damage human tissue 74

What’s on the horizon? • Bacteriophages • Shown to penetrate biofilms in the setting of pulmonary and vascular catheter infections 75, 76 • Evidence of clinical efficacy thus far comes mostly from animal models and case reports of treating XDR organisms • Lots of work to be done on potential for toxicity, dose, route, formulation…

Recap • Osteomyelitis is primarily a clinical diagnosis – you cannot rely solely on culture, path, imaging or typical findings of infection • Hardware infection behaves very much like OM. The key difference is that you are much less likely to sterilize infected hardware • We probably underrecognize and undertreat most osteomyelitis and hardware infection • When it comes to treatment duration, don’t “set it and forget it. ” Use clinical endpoints. • Remove infected hardware and necrotic bone whenever possible • Use adjunctive rifampin with susceptible staphylococcal hardware infections • If it won’t heal, it needs source control, a change in antibiotics or revascularization • There is a time and place for indefinite antibiotics

Questions?

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