Okay, you still see the screen, correct? Still see the screen? Somebody can confirm you see the screen slides? - Yes, yes. - Okay, perfect, great. Okay, thanks. Okay, so generally when we talk about bone and joint infections and the background, we separate into acute bacterial arthritis. And usually the distinction is gonococcal versus non-gonococcal infections. Osteomyelitis and prosthetic joint infections. This is the typical way that the infections are distinguished. If we start with acute bacterial septic arthritis, you've probably seen cases of this already. It's acquired from, it can be acquired from the hematogenous infection, either through direct joint inoculation or contiguous focus. Most infections are monoarticular. So that's an important distinction that would separate it from like a reactive arthritis. It's usually a monoarticular infection, not polyarticular. The most common joint affected is the knee, but it can also affect the hip, the shoulder, elbow and ankle and other joints. And as you probably know, the most common microbiology, Staphylococcus aureus and Streptococcus species. But you can see gram-negative pathogens in neonates, the elderly, IV drug abusers and even immunocompromised. Gonococcal arthritis has actually been decreasing in incidence overall with better diagnosis and screening and partner notification, but it's still important to recognize and it's usually the patient's history that is suggestive that makes you think that you could be dealing with gonococcal arthritis. So acute septic arthritis, usually clinical presentation, monoarticular pain, warmth and swelling of the infected joint that's very acute. The patient often has an inability to ambulate or put weight on their joints. They will often have fever, but there are mimics of acute bacterial septic arthritis, celiitis, bursitis, inflammation of the sac, the fluid that surrounds the joint that protects the joint can become inflamed. And it's a sterile inflammation. It's not a septic inflammation. Of course, inflammatory arthritis, either because of gout crystals or pseudo gout and rheumatoid arthritis, although typically rheumatoid arthritis will present a reactive arthritis will present with a bilateral presentation or polyarticular. So disseminated gonococcal infection that leads to septic arthritis often has a history. This is a classic history that was just presented in the New England Journal of Medicine a couple of years ago 20 year old woman presents to the emergency room with a rash on her arms, legs, trunk and scalp that arose that morning. She has complaints of muscle aches, fever, pain in both of her ankles. And importantly, two weeks earlier, she had a history of vaginal intercourse with a new partner without protection. The physical exam was notable for these erythematous pustules on her wrist and fingers and also on her trunk and scalp and on both ankles. She also had some mild swelling and pain with passive motion in her ankle and tenosynovitis in the tendons of both ankles. So this is sort of a classic history of disseminated gonococcal infection and gonococcal arthritis. So blood cultures can be taken. A lot of times blood cultures will be negative unless it's early in the course of disease. These were positive. You can see the grand negative diplocoxide and was identified as a nice serogonorrhea. Of course, after taking blood cultures, ceftriaxone was started with azithromycin for the cover of the chlamydia. And we always consider empirically covering. And of course, when her blood culture was positive it was confirmed as disseminated gonococcal infections. And so usually the patients have a very rapid response to therapy, but in some cases they may require arthrocentesis for recovery if they have an infusion in the joint. So in this patient, three months later, she was feeling well with no recurrence of skin lesions or joint pain. So in terms of non-gonococcal infections, the most common are going to be staphylococcus. Usually this can occur in both healthy and immunocompromised patients. Certainly patients with catheters, IV drug use, this may be a predisposition for staphylococcal infection. Group B streptococcus are more commonly seen in patients with poorly controlled diabetes or malignancy. Pneumococcal infections in patients with splenic dysfunction, 'cause they do not remove encapsulated bacteria. We can see pseudomonas septic arthritis in patients with diabetes. It's often a mixed infection, polymicrobial, but also immunocompromised. Any patient with bacteremia or had trauma with water exposure, pseudomonas and erymonas can be problems, especially brackish water. Salmonella is a cause of septic arthritis, especially patients with HIV, but also sickle cell disease. When patients have the infarction, the mesenteric veins in the gut, but also in the bone, they can develop a nidus for when they develop bacteremia of salmonella or developing a bone infection. You can also see things like eichenella and peptostreptococcus in people who have a contaminated wound because of a human bite or bad dentation and they have bacteremia, or they are licking a needle during IV drug use. Of course, you can see pathogens associated with cat and dog bites, pastorella and catenocytophaga. And microplasma ominous can be seen in people who've had, for example, a colonoscopy or recent gastro urinary tract manipulation, sometimes in immunocompromised and postpartum septic arthritis. So obviously this is considered an orthopedic emergency because there can be rapid damage to the cartilage and joints so it should be considered in any patient with monoarticular or polyarticular arthritis, and especially if the patients have recent joint surgery, if they have preexisting rheumatoid arthritis, so they have damage to the joint and cartilage that can serve as a nidus for seeding of bacteria. The older the patient is also with degeneration, there's risk of seeding damaged bone and also patients who have incombinant skin lesions or diabetes. We have to think about acute bacterial arthritis or septic arthritis. So the diagnosis is going to usually be based, you're going to take blood cultures, a metabolic panel, ESR and CRP, blood cultures, preferably two sets, this will be positive in up to one half of the cases, and arthrocentesis, which is the main diagnostic procedure. And of course, what we're looking for primarily is inflammation and the white blood cell count, is this normal or non-inflammatory arthrocentesis, or is there inflammatory or septic arthritis picture where it's especially in septic arthritis, it's very opaque and cloudy, very high white blood cell counts, and most of these are going to be poly. So then the culture will be positive. That's what distinguishes septic arthritis primarily from inflammatory arthritis, but also usually the white blood cell counts are much higher. So the arthrocentesis plays a major role also in reducing the effusion in organisms. Sometimes arthrocentesis is necessary for the therapeutic response because the joint space is actually a sort of anatomically privileged site in terms of antibiotic penetration. So arthrocentesis also helps with the response to antimicrobial therapy. Now, if the patient does have gonococcal arthritis and the blood culture is negative, of course, direct testing of the urogenital tract, the PCR, in addition to arthrocentesis may help establish the diagnosis. This does require, of course, special culture media. And when the patient has gonococcal arthritis, many times the cell counts, the white blood cell counts are not as high and blood cultures will have a lower diagnostic yield. So sometimes this diagnosis is missed, but it has to always be considered, especially in a patient who has a history that's suggestive that they may have gonococcal infection or potentially disseminated gonococcal infection. The good news is usually, as we saw in the case, the response is usually quick to antimicrobial therapy. Of course, there's always a possibility of resistance to, for example, third-generation cephalosporins or fluoroquinolones, but typically the response is quite rapid. But sometimes the patients may have persistent infusion in the joints and they require recurrent aspirations. Imaging ultrasound can help identify effusions in the knee, X-ray can show joint space widening, although sometimes it may not be as easy to appreciate, but especially in places like the hip where it may be harder to see the effusions, ultrasound can be very useful for helping image the effusion and its size and helping with the arthrocentesis. CT and MRI plays a very important role in also establishing if there's contiguous osteomyelitis and joint space effusion, so which would establish the need for prolonged antimicrobial therapy. It's also important to consider what are some of the other causes of non-gonococcal arthritis that tend to have more of a sub-EQ presentation. In the venator region, we have tick-transmitted Lyme disease that can cause infections through Borrelia burgdorferi, which is sort of a late-stage monoarthritis, usually affecting the knees, but patients start with fevers, rash after a tick bite. The synovial fluid is sampled when they develop the monoarthritis, typically affecting the knees, and it's tested by PCR to confirm the diagnosis, but this is once again, a diagnosis that could be missed, but it's especially important to think about in the spring and summer months, especially here in the venator region. I was out actually mountain biking in the Prosecco Hills last weekend, and I came back with a bunch of ticks, so definitely something to consider here. The treatment, of course, is different. Doxycycline or amoxicillin or cefuroxime for 30 days, or IV ceftriaxin if the patient doesn't respond. Then, of course, you have to think about some of the more red herrings, but important causes, things like Pott's disease, mycobacterium tuberculosis, usually affecting the large joints like the hips and knees. So this has to be considered or non-tubercular mycobacterial infections if a patient's had direct trauma or an immunocompromised patients who have disseminated disease. Fungal infections can also cause osteoarthritis, much less common, but anytime a patient has candidemia or fungemia, there is risk for Canada, Canada fungal joint space infections, and this would be established, once again, with arthrosynthesis and culture, hopefully the beta-D-glucan test. I don't know, you could say it's necessarily specifically effective for establishing the diagnosis 'cause there's going to be risk of false positives, but it can be a tool to help you make this assessment. There's other fungal pathogens that have a propensity to disseminate to the joints, including some of the endemic fungal pathogens like blastomycosis, cryptococcus, cryptococcus is not an endemic fungal infection, but blastomycosis, coccidiomycosis, cryptococcus, some fungal diseases that you get through direct inoculation, the classic rose handlers disease or sporotrichosis caused by sporotrichosis shenekei, where you puncture your finger or your hand with a thorn and inject fungal spores, sometimes you can get a joint space infection. So this typically is a disease that will require prolonged antifungal therapy and surgical debridement for a clinical response. Now, sometimes you can see reactive arthritis or arthritis that develops after viral infection, after acute HIV, hepatitis B and C, parvovirus, rubella, chikungunya virus, arboviruses such as Ross-River virus, et cetera. But the differentiating factor in terms of the presentation is usually symmetrical polyarticular pattern. Of course, if you do an arthrocentesis, you may not see the same degree of infusion, you will not see the huge shift in polys, the high white blood cell counts. And so the pathogenesis has been debated, is this a direct infection of the viruses versus an immune complex formation after immune response to the virus? But the point is, this is a generally a self-limited problem that requires only supportive care and non-steroidal anti-inflammatory agents. Occasionally will cause prolonged chronic arthritis after these viral infections, but it's generally a self-limiting problem. We can also see reactive arthritis or Reiter's syndrome after some infections such as enteric infections with Shigella, Salmonella, Yersinia, or Chlamydia trapeumatis infection. So the patients develop a sterile inflammation of the joints and it's been associated with a specific human leukocyte antigen type, HLA-B27. So this usually, Reiter's syndrome usually affects younger adults who develop these asymptomatic oligoarthritis and then often they have extra articular manifestations such as uveitis, urethritis, conjunctivitis. So the classic saying is the patient can't see, they can't pee, they can't climb a tree. And this is something that's well-described after Shigella, Salmonella, and Yersinia. Once again, it's sort of a self-limiting problem and generally treated symptomatically with non-steroidal anti-inflammatory agents. Okay, if we move to osteomyelitis, here we get into sort of three major categories. Is it osteomyelitis is developed via hematogenous spread versus contiguous infection versus a direct inoculation. And you can put pediatric osteomyelitis as a separate category, but it's generally hematogenous spread. So this is a hematogenous spread, obviously through the Vogel classification is a secondary infection. Patient had bacteremia, it seeded either a price of previous damage to the bone or became sequestered in the bone and set up a localized infection that then becomes destructive and progressive. Contiguous is when the patient has bacterial inoculation from an adjacent focus, such as post-traumatic disease and open leg fracture or something, and they develop contiguous infection or they have cellulitis that progresses to osteomyelitis. And then we often can see bone infections in patients who have vascular insufficiency due to of course, most commonly uncontrolled diabetes, patients with diabetic neuropathies, peripheral vascular insufficiency or Hansen's disease leprosy. They have preexisting damage, they have damaged and ulcers to the leg and the poor vascular blood flow creates a propensity to develop deep wound infections that can progress to osteomyelitis. Another important factor in differentiating the infection is the duration of infection, is it acute versus chronic? Typically acute is defined as an initial episode with edema, formation of pus, vascular congestion around the bone and thrombosis of the small vessels, whereas chronic disease is a recurrence of an acute case where patients develop long arms of ischemia, necrosis and bone sequester. So if you look at this in terms of imaging, we're going to show some differences of this, but for example, contiguous spread from adjacent tough tissues and joints is usually polymicrobial. So a patient with a classic diabetic foot ulcer progressing to osteomyelitis of the toe or the foot, this is usually going to be a polymicrobial infection. It may involve both gram positive, gram negative and even anaerobes, whereas a direct inoculation, osteomyelitis, typically the microbiology is from trauma or surgery. It can be polymicrobial, more commonly monomicrobial and hematogenous seeding is almost always monomicrobial. So that can be an important consideration when you're selecting your therapy while you're waiting on cultures, for example. So of course, staphylococcus aureus is one of the most common causes of hematogenous spread of osteomyelitis. So there's an initial infection localized to the cortical region. There's a small abscess that forms, the abscess enlarges and progresses to the subperiosteal space with lifting of the periosteum. And then eventually a sequestrum, an avascular necrotic region forms in the bone that sometimes forms a sinus track, allowing pus to escape outside the bone. And sometimes the sinus tracks will follow outside the skin. So you will have drainage outside the skin from the infected bone. So this is a classic presentation. Acute hematogenous osteomyelitis, especially in pre-puberal children is the most common form of osteomyelitis, but it can also be seen in elderly patients, other patients who are predisposed to bacteremia, IV drug abusers, patients with indwelling central venous catheters, most commonly caused by Staphylococcus aureus. In children, the disease usually is a three to six week course of antimicrobial therapy. Less than three weeks has been associated with higher failure rates. So one of the obviously main themes right now in an infectious disease is shorter is better, trying to get to shorter therapy. Classically, the dogma for osteomyelitis is four to six weeks of therapy, or even 12 weeks of therapy. But acute hematogenous osteomyelitis in children is one setting where less than three weeks of therapy has actually been associated with higher rates of clinical failure. There are some other classification schemes of osteomyelitis. Czerny and Mader proposed a classification that's somewhat similar initial site of infection in the periosteum. Then the problem once again, as the infection progresses, the blood supply is blocked. You have this subperiosteal abscess that then can form push and fistula with a sinus track that can be involved in causing a diffuse osteomyelitis. So the common principles consistent with all osteomyelitis is that the diagnosis is usually first suspected on clinical grounds. Patient has a new onset pain, they may have fever, they have problems putting pressure on the leg or affected joint, and a X-ray can be performed, although findings of osteomyelitis on X-ray can be delayed as much as two weeks. So CT, PET CT or MRI have much higher sensitivity. And in fact, negative results from CT or MRI actually rule out the infection. If a patient has hardware, prosthetic material, prosthetic joint, this may preclude an MRI and it can create artifacts with the CT. So this sometimes makes imaging a little bit more difficult. We really want to identify the pathogen. We don't want to treat necessarily empirically. So surgical sampling or needle aspiration under radiological guidance is almost always needed. This helps identify the pathogen, helps identify the length of therapy, identifies potential resistance, swab cultures from draining wounds or sinus tracts. Sometimes this helps establish the diagnosis if it's MRSA, but if it's a non-staph aureus infections, they may not always provide the true pathogen. It may give you coagulates negative staphylococcus. We also, of course, are going to look at inflammatory markers by themselves. They're not diagnostic, but they can be useful to follow over time in terms of assessing response to therapy for osteomyelitis. So as you're probably aware, the most common pathogens are staph aureus. You can see coagulates negative staphylococci, certainly in some cases, although less virulent. You occasionally will encounter streptococci, enterococci, sometimes enterococcus in the setting of a polymicrobial infection, pseudomonas, enterobacteriaceae, anaerobes, and we mentioned tuberculosis. The rare pathogens are things like MAC, rapidly growing mycobacteria, the endemic fungi or dormant morphic fungi, and other fungal pathogens. And then we have some other things you have to think about like prophyluma, whipii, and salmonella, actinomyces, and brucella, which brucella is kind of an important pathogen in the Mediterranean, especially the Southern Mediterranean, but it is a diagnosis that's sometimes missed, and it's a diagnosis that a clinical history can give you a strong suspicion that you may be dealing with brucelliosis. So if you're seeing a young farmer who has sheep and cattle, maybe that's involved in cheese production from Messina, for example, and they complain of a flu-like illness that then follow with joint pain or back pain, and especially if they say they have brothers or a father that also has joint pain, this really should make you think about, could I be dealing with brucelliosis? And epidemiological studies have suggested that it's through the contact with the cattle and sheep, infected sheep, that there's this risk. The calculated occupational exposure risk is 25%, but is it associated with just day-to-day contact? Is it associated with the time animals are slaughtered, for example, prior to, when does it peak prior to the holidays? So prior to Christmas, December, January, or Easter. And it turns out, actually, the peak incidence is in May and June. We're in the peak brucelliosis period. And this seems to suggest that it may be due to the production and consumption of fresh cheese. So fresh milk and fresh cheese can be transmission of brucelliosis. So it's important to suspect this, and especially in somebody who has occupational or a history that may suggest this brucelliosis, because of course, the treatment is different than staph aureus. You need different cultures, you need PCR, you need different diagnostic tests to establish this. So it's always something important to consider as a differential cause of osteomyelitis. A big part of response in some cases is going to be on surgical debridement and adequate drainage of infected tissue. You need extensive debridement of all infected tissue. We're going to talk about joint, prosthetic joint infections. In many cases, you will need removal of hardware. And so a lot of times, what's interesting is this idea that you have to give four, six, or 12 weeks of therapy is now actually being challenged. Where it's being challenged with osteomyelitis is when you can do very good surgical procedure, and you can put in the bone graft or bone cement antimicrobials. There was a study just presented at ECMID that suggested you can get by with very short duration of therapy, provided you have good surgical cleaning of the infected bone and debridement, and you place a licensed bone filler with antimicrobials in the space. And we'll come back to that study. But I think it makes the important point that a lot of the failures that we see in the treatment of osteomyelitis and the relapse can be related to ineffective surgical debridement. And if you look at actually some other countries, for example, in England, they have areas of excellence where all they do is manage osteomyelitis and bone and joint infections. And they have surgeons who all they do day after day is doing debridement and fixing problems with osteomyelitis. So there is something to be said for the expertise in surgical management of this disease to give antibiotics the best choice of working. What about patients who develop open fractures moving from hematogenous disease? You can see osteomyelitis develop in up to one quarter of patients at the fracture site. When patients develop infection, this may lead to non-union of the infection site. Chronic osteomyelitis may require amputation. Of course, this most commonly is a problem in the tibia and fibula. So it's very important that open fractures undergo aggressive wound irrigation, debridement, patients receive parental antimicrobials, they have stable fracture fixation, and they have soft tissue coverage of the exposed bone. This reduces the risk of developing the secondary osteomyelitis. Typically though, what's important to point out is the osteomyelitis will develop often several months after the open fracture. So if osteomyelitis develops, patients will require additional surgery, debridement, and prolonged antimicrobial therapy. And because this is more of a subacute course and the extent of disease, in many cases may require up to six months of therapy. So in this picture, you can see the CT image of this person who had non, the femur fracture did not unite after six months after the intramedullary nailing, and the surgical cultures grew pseudomonas and propionibacterium acne. So really is a serious complication that prevents the healing of these severe fractures. One of the most common types risk for osteomyelitis, of course, are gonna be diabetic foot infections. This is a direct extension from the diabetic foot ulcer to the bone. Whenever somebody has exposed bone, the probe to bone test, when you probe the wound and you can reach bone, the sensitivity of the patient actually having osteomyelitis, that test has a sensitivity of 60%, but a specificity of 91%. So if you can touch bone with a probe in the wound, there is a good chance the patient will have osteomyelitis. So obviously patients who have poor glucose control, who have peripheral vascular disease, antecedent trauma, chronic ulcerations, these are patients who are going to be at risk. Often these infections are polymicrobial. The big debate is always, do you need to cover pseudomonas? Many people say in the beginning, no, you do not need to cover pseudomonas unless the patient has been involved with water, dirty water, or they've failed previous antimicrobial therapy. So that's sort of a stewardship pearl. But the decision to give antibiotic therapy is based on the severity of infection and the risk of resistance. So generally we're going to cover staphylococcus and streptococcus species. We only cover MRSA if the patient had a previous history of MRSA infection. We wanna cover some gram negatives, but pseudomonas is usually patients who've had clinical failure on non-pseudomonal antibiotics, or they've had these wounds exposed to water, and only anaerobic coverage is usually needed if there's clear tissue necrosis and ischemia. So this is evaluated as in other cases of osteomyelitis with laboratory testing, we look at inflammatory parameters. Patients usually will not be bacteremic, they may not have fever, but on the imaging they usually will have bony erosion that by the time you're seeing them, this usually happens within two to four weeks after development. But a negative X-ray does not rule out completely osteomyelitis. MRI can detect the tissue infection if they have associated abscesses, and it can also detect osteomyelitis early, but this is something that may take longer to get the patient scheduled for. So only if the patient has fevers and chills at the time they have the osteomyelitis would a blood culture probably detect the pathogen. If the patient's clinically stable, sometimes we can withhold empiric antibiotic therapy until culture data are available. Superficial swabbing of the wounds a lot of times is not thought to be very useful, but once again, MRSA, Staph aureus, is usually taken pretty seriously, especially if it's MRSA. But like a classic approach towards multidisciplinary care for diabetic foot ulcers, when the patient comes in with a diabetic foot ulcer, is there any signs of inflammation or purulence on the clinical exam? So is it red, warm, is there swelling, is there friable tissue, is there any drainage or odor? If not, usually these patients can go to just local wound care with follow-up and reducing pressure on the effective area. A lot of times we try not to go immediately to antibiotic therapy, but if the patient does have this evidence of erythema, drainage, and odor, then we have to assess the ulcer, the extent and depth. We do imaging, we do the probe to bone test. If it's been present for more than a month, if it's recurrent, if the patient's had any prior amputations, there's a good possibility the patient does have underlying osteomyelitis. So we're going to need to do imaging, we're going to have to do an assessment of peripheral vascular disease, do they have enough blood flow for wound healing, or is there going to potentially need amputation going to be needed? So this is going to require consultation of your surgical colleagues. And then empiric antimicrobial therapy, if the patient's acutely ill, if they obviously look septic, if they look rigors and chills and fever, you could consider starting empiric antimicrobial therapy, but generally we'd like to get cultures if they're more clinically stable before we start empirically treating. Vertebral osteomyelitis or spondylitis, obviously is an infection of the vertebral bodies and adjacent disc spaces. Interestingly, this is the number one cause in the United States of lawsuits against infectious disease physicians because the diagnosis is missed. The patient is treated with staphylococcus bacteremia, the blood culture is clear, maybe the catheter was exchanged, hopefully, and the patient seems to be clinically stable, the antibiotics are stopped and then they develop back pain and it's not taken very seriously. And then the pain becomes worse and progressively worse. And then eventually as they have more destruction, imaging and MRI, for example, establishes that they have spondylitis. They have infection of the lumbar spine or the thoracic spine. So when it's missed, if it's missed very late, the damage is more extensive and the patient has more disability. So this is why it's a big problem in terms of lawsuits. So we always wanna think about the risk for vertebral osteomyelitis in a patient who's had bacteremia because it's usually hematogenously spread. Obviously, the patient's had trauma or if they've been having intrathecal injections, there could be a contiguous spread. Sometimes there's extension in patients who have GI tract bleeds or esophageal perforation, but the most common scenarios is hematogenous spread to the bone. Typically, most commonly the lumbar spine, more so than the thoracic or cervical spine. Now, in patients with brucelliosis, back pain, once again, if we go back to that farmer, if he's complaining of back pain, you could see lumbar, but many times, one of the times, an important clue is lumbar sacral pain, pain around the sacral region. So it tends to be more of a predominance with brucelli or osteomyelitis in the sacral region versus the thoracic and cervical regions. So the main risk factors for infection that have classically been identified, of course, are things that are people who are predisposed to bacteremia, but also diabetes, corticosteroid injections for the local contiguous, people who've had previous spinal surgery. Usually, this is a monomicrobial infection, usually gram-positives, so we think staph aureus, the top of the list, but gram-negative infections may be seen if the patient's been bacteremic, sometimes involving the lumbar spine. 30% of patients may have neurological complications. And the clinical presentation, what always makes this difficult is it often starts very subtle. Back pain, for example, in our patients who've been in the hospital or the hospital bed for a long time, it persists and worsens over time, does not respond to conservative management, then they have fever. Eventually, the patient is imaged, they may have blood cultures, and a diagnosis is established. So these patients will often have elevated inflammatory markers. They may have positive blood cultures if they have fever, especially fever with rigors or chills. If you catch it, the blood cultures will be positive, but we're going to wanna do, to really establish the diagnosis, an MRI is important because X-rays may not demonstrate erosive changes until latent disease, and we're going to wanna bone or tissue biopsy to try to establish the culture. Are we dealing with a monomicrobial infection, polymicrobial infection? What's the sensitivity? Of course, if the patient's been bacteremic, you have a pretty good clue of what may have caused the vertebral osteomyelitis, but sometimes you can be fooled. So generally, it's a good idea to hold antibiotics for a day or two until you can do this biopsy. If you have to, you can give one or two doses that's been shown not to affect necessarily the sensitivity of biopsy. Some people say at the time you do the biopsy, you can also consider doing a blood culture because sometimes blood cultures will become positive while you're doing the biopsy. And then once you have the blood cultures and the biopsy taken, you can consider starting empirical therapy against the most common pathogens based on what your differential diagnosis is with the clinical history and the risk factors and whether the patient had antecedent bacteremia. Most cases can be initially treated with six weeks course of parental antimicrobial therapy without surgery. Although the more advanced the disease is, the more unstable the spine, surgical intervention is going to be more important. Staph aureus, MRSA, MSSA, cause more than 50% of the cases, gram-negatives in about 30% of cases. And then you have the less common causes such as group B strep, pseudomonas, salmonella, and candida, for example, in patients who have the risk factors. The other causative organisms, less common things, once again, Pott's disease, usually a thoracolumbar disease that usually involves contiguous vertebrae that has a unique pattern of spread along the spine. It's different than classic pyogenic vertebral osteomyelitis or spondylitis. So some aspects of the imaging may be more suggestive of tuberculosis. And as we mentioned, the greater probability of sacral involvement with brucellosis would be a sign that you may be dealing with brucellosis versus, for example, the classic staph aureus. So one of the classic dogmas is we give intravenous therapy, and we'll come back to this. Do you always have to treat with IVs? Can you use oral therapy? Minimum classically we say is six to eight weeks. Some people say 12. Can you get by with less? We'll come back to that. Of course, atypical organisms often will require extended courses of therapy. The response will be slower. So brucellosis requires minimum of 12 weeks of therapy. Fungal infections, acid fast bacteria can require months of therapy, and the response can be quite slow and may require surgical treatment. So there has been a lot of interesting studies now going back to this question of how long to treat. Can you use shorter course therapy, six versus 12 weeks? And in the case of six versus 12 weeks in patients with pyogenic vertebral osteomyelitis, Bernard and colleagues performed an open-label non-inferiority randomized controlled trial comparing a six-week regimen versus a 12-week regimen. And if you look at the difference in the proportion of patients in terms of cure rates, there was suggestion that a six-week regimen was sufficient in most of these patients in terms of the clinical cure and the clinical cure without need for further antimicrobial therapy and without requirements for subsequent treatment. So this is why we get this at least six weeks of therapy. And I think that's one advantage of where a shorter course regimen has gone back and been studied and shown that six weeks is usually enough. Obviously, if the patient has slow response, then we would consider using longer prolonged therapy. One of the most difficult areas of bone and joint infections are prosthetic joint infections. Of course, the pathogenesis, what makes bone and joint prosthetic joint infections is the formation of biofilm on the prosthetic joint. You know, at the interface of the implant and the cement, you have either a hematogenous seeding or bacterial colonization that occurred at the time the prosthetic joint was put in. And as the organism attaches to the prosthetic material, it forms this glycocalyx, this matrix that protects it from the immune system, protects, impedes antibiotic penetration. Bacteria deep inside the biofilm are not growing as rapidly. They're because of the low oxygen tension, the less nutrients, they kind of become zombie like bacteria so they will not be killed as rapidly, but they can always re-emerge when they come into higher oxygen tension or if the biofilm is disrupted and can release and cause infection of visceral organs or other bones or contiguous tissue. So the characteristic features of this infection, and it can involve any joints that are replaced, the knee, the hip, the shoulder, wrist, ankle, fingers, is joint pain, erythema with edema, you as the infection progresses, it may cause inflammation and loosening of the prosthetic joint. And then patients can develop this draining sinus tract that communicates with the joint space or arthroposte leading to inflammation. Excuse me for one second. Okay, somebody's knocking on my door. So the incidence of this infection is actually increasing both knee and hip infections. If you look at the actual incidence, it occurs in about one and a half to two and a half percent of all hip replacements, two and a half percent of all knee replacements. If a patient has a revision, they go back and have the joint replaced, there's going to be associated with a greater risk of infection. The prosthetic joint infections are divided based on the presentation. The timing is early within three months. Usually this is believed to be an infection that's acquired because of the time of surgery, that the pathogen was actually implanted with the joint. So it's a contiguous spread. When it's delayed, usually the onset is between three to 24 months, and this can be also contiguous, whereas a late onset is usually hematogenous spread with joint involvement. So there is a distant infection and it seeded the prosthetic joint. So of course, the risk factors for this infection are going to be things that can be divided into preoperative risk factors. The patient had prior surgery, they have prior damage to the bone, they have diabetes, they're obese, rheumatoid arthritis, immune suppression, anemia, some of these other comorbidities, they're going to be at higher risk for developing prosthetic joint infections after the joint replacement. If the patient required allogeneic blood transfusions, they had a prolonged operative time. If you're doing simultaneous both knees, for example, there's going to be greater risk if you're doing more joint replacements. And if the patient developed a surgical site infection or they have a large hematoma or bacteremia, of course, this is going to be risk for prosthetic joint infection. So sudden onset of pain, painful prosthesis, erythematous joint, draining sinus tract or wound drainage, turbulence involved without coming out around the wound. There are some mimics, you can't have metalliosis, aseptic loosening, you can develop crystals that can cause some pain with the joint, but this is generally going to be an aseptic problem. So these are diagnosis of exclusion. You can imagine the most common causative agents, especially when the organism is implanted with the joint is going to be a lower virulence organism like coagulase negative staph from the skin, the staph aureus, it's typically a much more aggressive infection, but if the patient's been bacteremic with streptococcus, enterogram negatives, Brucella, et cetera, you can of course see hematogenous seeding. You can also see acute of bacterium, propion bacterium organisms, for example, and there's a predisposition of propion bacterium with shoulder replacements. It's much rarer with hips and knees, and I don't know entirely the explanation for that. Of course, as the patients received antibiotics before, it may be hard to establish the diagnosis, but we want to establish a microbiological diagnosis. Once again, with arthrocentesis, it's a gold standard for diagnosing prosthetic joint infection. If we think it's a hematogenous spread, of course, then the question is, where was the source? Does the patient have, did the patient have bacteremia from unexplained source, such as do they have endocarditis? You might consider doing transesophageal echocardiogram. You're going to do imaging of the joint to see the loosening and the damage, but arthrocentesis will be the gold standard in diagnosing. We want to hold antibiotic therapy until this procedure can be performed, and we're going to do a differential gram stain culture and crystal analysis for gout and pseudo gout. You can also look at molecular biomarkers like alpha-defensin, and if, of course, if the prosthesis is removed, then we can also directly culture this and sonicate it to try to disrupt the biofilm and make a microbiological diagnosis. So the treatment of prosthetic joint infection usually follows a concept of debridement, antibiotics, and implant retention. There are different types of strategy of DARE. There's a single surgery approach where you do irrigation debridement. You exchange all the materials and you give prolonged IV therapy directed at the pathogen, eventually switching to an oral antimicrobial. In many cases, the antimicrobial therapy may contain rifampin if it's a staphylococcal infection because rifampin has activity in biofilms, and we're going to talk about the controversies with rifampin, and this can be continued for 6 to 12 weeks, and in some cases, some patients may require more chronic duration of therapy. Other approaches are a one-stage exchange or a two-stage exchange. A one-stage exchange is done when the patient does not have a sinus tract, the patient has still adequate bone stock, so you can do debridement. You could do a complete prosthetic exchange with antimicrobial loaded cement, put the prosthetic joint back in, and then you do therapy as above. Many of these patients will not require continued suppressive therapy. A two-stage exchange is going to be a situation where you take out the, you do the debridement, the prosthesis is removed, and you put in a spacer, a temporary spacer that often contains antimicrobials, and you're going to treat, and this is usually patients who have much more advanced disease, more chronic infection, patients with a sinus tract, and more difficult to treat organisms, so here's a situation before we put the prosthetic material, we're going to have this implant-free period. This is why it's called a two-stage exchange, at least four to six weeks of therapy, followed by two weeks of an antimicrobial-free period to ensure the patient doesn't develop recurrent fever, recurrent erythema at the site of infection, and then the patient undergoes a second surgery, the spacer removal, prosthesis is put back in, and then in some cases, patients may even receive post-replacement prophylaxis. And then the other approach that's sometimes used is a patient who's not eligible for exchange, they may have a resection arthroplasty, so in severe cases, this could require even amputation. So sonication is a way that you can remove the prosthesis, you put the hardware in Ringer's solution, you sonicate it for five minutes, this disrupts the biofilm, you can then plate this on auger, aspirate the sonicated fluid, centrifuge it, and this can sometimes give you a microbiological diagnosis if it's in biofilm. So prosthetic joint infections are another big area of debate, six versus 12 weeks for treatment. Is it the same as, for example, spondylitis, or ventibular osteomyelitis? So this was a large study, once again by Bernard and colleagues, a French group that took 410 patients and randomized them to receive six weeks of antibiotic therapy versus 12 week. This include patients with multiple different types of DARE procedures, but they had very long follow-up, two years follow-up after their surgery to assess the outcome. The patients were relatively well matched between the six and 12 week group. And if you look at the most common regimens, usually they got IV antibiotic therapy for nine days, but then they were switched to an oral antibiotic regimen, usually rifampin plus a fluoroquinolone. This is the regimen that's most frequently associated with activity against MSSA and has good anti-biofilm effects. But there were some patients who received clindamycin, some who received trimethoprim, sulfonylmethoxazole, and a few patients who received amoxicillin or clavulanate. But unlike with spondyomyelitis, we see in this situation, some evidence that patients did actually better with 12 weeks of therapy versus six weeks of therapy. If you look at all patients, and this included, if you stratified it by patients who underwent debridement with two stage and one stage revision, it all trended towards favoring the longer duration of therapy with the 12 week regimen. Although of course, some of these numbers are smaller, so they were not statistically significant. But there's an example of what, if you look at the longer duration of therapy actually seemed to be more important for treating patients with prosthetic joint infections versus six weeks of therapy. So that's one situation where shorter hasn't necessarily been shown to be better. However, there was this study published at ECMID that was really quite impressive done by an orthopedic expertise centers in the UK called the Solario trial that looked at short versus long antibiotic regimens in patients with orthopedic infections. And they were asking the question, is it possible to reduce to four weeks more of orthopedic infections to seven days or less if the patient undergoes surgical debridement and a licensed local antibiotic carrier, like a bone eluding defect filler, such as Ceramide or Ceramide 5 are implanted inside an infection. So this is not surgical debridement with sprinkling vancomycin or sprinkling something in the wound. This is actually a license approved carrier that releases antibiotics slowly over time at the site of infection. So this is a very aggressive and bold study, seven days of taking longer antibiotic, systemic antibiotic therapy and shortening it to seven days provided the patient has this bone eluding cement. So they took 500 adult patients with orthopedic infections, followed for one year. Now this is orthopedic infections. This is why it's four weeks, not so much infections seen with the joint replacements. But basically, and this has not been published yet, it was just presented to Ekman. But basically what they found that the non-inferiority margin they were shooting for was 10%. And what they found is in patients who got the short course therapy without the, this is once again, not prosthetic materials, this is just osteomyelitis. If they had good surgery, if they had the antibiotic carrier placed, patients who had only seven days of IV therapy plus the bone cement had equivalent outcomes. They were within 10% non-inferiority margin. And actually the patients also had less diarrhea, shorter length of stay in the hospital and fewer adverse effects. And I think that's kind of important, interesting point. After you've had a osteomyelitis and you've had this surgery, the last thing you want is to have to go back and forth to the bathroom when your leg is in pain with diarrhea. So there was also less clostridium difficile, but that was not quite statistically significant. So I think there's this very interesting trial now showing that maybe one of the ways, the pathway to getting to shorter antimicrobial therapy is to have good surgery and good local prolonged antibiotic therapy. And that may allow us to give us a shorter period of systemic therapy. So we don't have to do this six or 12 weeks, but this is something that needs to also be investigated in patients who have the implanted, the device related infections. Now, I just want to finish with a couple of points about dogmas and controversies. One of the things we were always taught, pick antibiotics with good bone penetration. And there certainly are antibiotics. Some antibiotics are better than others. It's penetrating the bone. Where did this dogma come from? Seems to have come from older review articles published in the 1970s that described the concept of antibiotic bone penetration as being important. However, the problems with interpreting antibiotic bone penetration data is usually this is done in healthy volunteers. Somebody who's undergoing, for example, an elective hip surgery. So they're given a course of antibiotics that's of interest. The, when the hip surgery is performed, a section of the bone is sent to the laboratory. It's homogenized and it's ground up. And then they analyze the concentrations of the antibiotic by mass spectroscopy or high performance liquid chromatography. So the problem is you're mixing this. Number one, this is patients without infection. This is an, there's an uneven distribution of antibiotics between different bone components. So it's not clear this homogenization and measuring the total concentration is really reflecting concentrations at the site of infection. It's never been proven to be associated with higher success rates in osteomyelitis. Also, this is usually done with a single time point. Patient gets the antibiotic, the surgery is performed. They may, maybe they do a blood concentration at the same time and they compare blood concentration to the bone concentration. Well, that's a single time point. Sometimes there's what's called hysteresis, a delay from bone to blood. So depending on your timing, you may misestimate the ratio of penetration. So actually the way you would have to do this is do multiple samples and do area under the curve. So recent systematic reviews have found that most antibiotic classes achieve really similar bone to serum ratios with the exception of oral penicillins and cephalosporins. And even those drugs have had similar clinical efficacy. So I think this idea of that you have to have that antibiotic with good bone penetration is something that's really being challenged that this dogma is really not proven. The other dogma we classically hear, you have to use IV. You cannot use oral antibiotic therapy or osteomyelitis. And we have a trial, the Oliva trial that compared oral versus intravenous antibiotics for bone and joint infection. Within seven days of starting IV therapy, patients were randomized, switched to oral therapy versus continuing IV. So you can see the curves here, patients who stayed on IV therapy versus patients who go on oral therapy. And if you look at the percentage of patients after randomization and continued antibiotic therapy, it was similar between the two groups. The baseline characteristics were similar between this trial. And if you look at the outcomes, the clinical outcomes, the clinical response based on intent to treat population, modified intent to treat protocol, all favored oral therapy. Patients who had oral therapy got out of the hospital faster. They had equivalent outcomes. It wasn't statistically better, but it definitely wasn't worse. And it actually sort of favored oral therapy. They also did this worst case sensitivity analysis that maybe was somewhat suggestive towards IV, but basically oral therapy was associated with shorter hospital stays, fewer complications. And if a patient can take oral therapy, you definitely can get them on oral. This is, we're trying to get towards shorter regimens, but the other main theme that we hear now in infectious disease is that oral is the new IV. And we have a very useful trial that supports that. It's still not the standard of care, but I think that if the patient can take oral therapy, we really should push that towards that. What are the most common oral antibiotics that are used? Most frequently planned oral antibiotics, excluding rifampin in this trial were fluoroquinolones with a combination sometimes of rifampin, but the outcomes did not differ significantly between groups that received intended IV versus oral antibiotic therapy. Now, rifampin is always an interesting question. There are believers and non-believers. The idea of using rifampin for the treatment of osteomyelitis and bone and joint infections, and especially prosthetic joint infections because of the biofilm is that rifampin penetrates the biofilm and has greater activity. And animal models also suggested greater cure rates. There were some small prospective trials that suggested benefits of combining antistaphylcoccal penicillins with rifampin, but none of those early studies included patients with prosthetic devices. We since have had randomized trials with rifampin plus either trimethoprim, sulfamethoxazole, rifampin plus lenazelid, rifampin plus clindamycin, rifampin plus fluoroquinolones, and the combination that always seems to be the most impressive is rifampin plus fluoroquinolones. There is some benefit with rifampin plus clindamycin, but rifampin, remember, is a cytochrome P450 inducer. It actually reduces clindamycin and lenazelid concentrations somewhat. So there is some concern that maybe the benefits of combining rifampin with these drugs may be somewhat impaired by reduced exposures. What's the dose? There's debates about the dose. Most people feel 600 milligrams once daily is enough. If you go with higher doses, you will see a higher risk of drug adverse effects, including hepatotoxicity, gastrointestinal intolerance, and in fact, patients, especially who are receiving higher dosages, there was a recent study, the Eve Rios study, that was presented at ID Week in 2025, compared lower doses versus higher dose, and what they found was equivalent outcomes. The patients who received 20 milligrams per kilogram of rifampin in the treatment of osteomyelitis had adverse drug reactions. In many cases, they could not continue therapy. Nico Cordes-Penfeld has written a lot of beautiful meta-analysis and reviews on the management of device-related infections, and one of his meta-analysis shows us pretty clearly that not all partner drugs are the same with rifampin. It seems that fluoroquinolone plus rifampin are the drugs that are associated with the higher probability of clinical response versus if you combine a non-fluoroquinolone antibiotic with rifampin. So generally, if you're going to use rifampin, the fluoroquinolone is the best combination partner for treating if you're going to use oral therapy. The caveats, there are several other important caveats for using rifampin. If you're going to use a junk of rifampin, do it following debridement, because rifampin does have a risk of a single mutation leading to resistance. So if you can reduce the burden of organisms with debridement, you'll reduce the risk of selecting for rifampin-resistant isolates. Pay very close attention to drug interactions. Rifampin is a very potent inducer of cytochrome P450, and this induction occurs rapidly. So if a patient's receiving direct acting anticoagulants or other therapies that are metabolized through cytochrome P450, you will see substantial reductions in serum drug levels, much faster clearance. And remember, drug interactions occur twice. Once when you start the antibiotic, once when you stop it. So if you stop rifampin, the drug interaction will reoccur. You're going to have to readjust the dose. So one of the most common problems we see now is the drugs like epixabam, the direct acting anticoagulants. And also hepatotoxicity can be a problem. What about the question of what's the optimal antibiotic therapy? There's a lot of interest, for example, in using some of the newer drugs like dalvovansin, because of the long half-life of the drug. Dalvovansin can be given in two doses and provide upwards of six weeks of effective exposures of drug. So this certainly would be a very appealing therapy to give. Two doses of the drug, you give a dose, you can maybe discharge, and then right before discharge, you give the second dose of the antibiotic, and the patient has sufficient drug levels for coverage of MRSA or MSSA for up to six weeks. There is a lot, as I can tell you, as an editor on JACK, we're seeing now lots of papers about therapeutic drug monitoring of dalvovansin. Most of these therapeutic drug monitoring studies are showing that the exposures to dalvovansin are sufficient to cover MRSA for up to six weeks, but some studies are actually suggesting that we should do therapeutic drug monitoring to minimize accumulation of the drug. But there is growing interest in using TDM as a way to consider this. There has been a recent trial that was presented last year at ECMED called the DOTS trial, which was looking at dalvovansin as a consolidation treatment. So the patient's received their initial induction antibacterial therapy, so anywhere from up to three to 10 days of their normal antibiotic. And then the idea is, instead of going to oral therapy, you give dalvovansin during a consolidation phase to provide four to eight weeks of therapy, or a patient can stay on a standard of care IV antibiotic for cefazolin, nafacilin, or vancomycin or daptomycin. Now, one of the things I'll point out, another study that was presented at ECMED was the SNAP trial that compared the antistaphylococcal penicillin, dicloxacillin, did not compare nafacillin to cefazolin for MSSA infections. And importantly, one of the things the SNAP trial showed was a much higher rate of nephrotoxicity in patients who receive antistaphylococcal penicillin versus cefazolin. So this, in many people's mind, has suggested that cefazolin should by far be our preferred drug of choice over nafacillin because of the better safety profile. But that was not, that included some patients with osteomyelitis, but it was mostly a bacteremia study. And so this followed patients up to eight weeks, and then a follow-up up to 70 days after a treatment. And if you look at the response rate, they use these DOOR criteria, where they're looking at not only clinical measures of clinical response, but also patient satisfaction, and also adverse effects, and including this all in the assessment of the response. And basically, dalbovansin was equivalent to giving as a continuum IV therapy for four to six weeks. So clearly, there's even some suggestion in terms of adverse effects that maybe dalbovansin had fewer adverse effects. So dalbovansin certainly is an alternative. It's an expensive alternative, but is an alternative way to provide persistent therapy for the treatment of osteomyelitis, spondylitis, and possibly even prosthetic joint infections for providing MSS, methadone-sensitive, or MRSA coverage for these patients. However, I will point out there's some also other interesting approaches. For example, our colleagues in Bologna have proposed based on their experience, or I think interests in antibiotics, some interesting approaches towards maybe giving maximal or optimizing therapy. And their question is, are there certain combinations or approaches that can be used to enhance clinical antimicrobial activity against osteomyelitis? So this paper published by the Bologna group said that, well, we should pick antibiotics based on bone concentrations, even though, as I pointed out, there's a lot of problems with bone concentration, but they also looked at what's the data on antibiotic film activity. And what they suggested is that they also looked at PKPD targets and some of our other drugs. And I'm just pointing, giving this as a possibility. There's really, these flow charts that they present, there's no good prospective randomized controlled trial data to support some of what they're saying. But for example, septic arthritis, they say combinations of daptomycin plus fosamycin or ceftibiprol. Okay, there's no evidence that supports that, but they think that that might result in a more rapid clearance. Once you have a negative culture, you can switch to oral therapy, monocycline rifampicin, or give that long-acting dalbovansin with rifampin. But this is sort of just their opinion. If it's a targeted therapy, if it's MSSA or MMSE, they're suggesting oxacillin or levofloxacin. I think many people would now say cefazolin based on the fewer side effects versus the antistaphylococcal penicillins. MRSA, they're suggesting daptomycin plus fosamycin or ceftibiprol. Once again, interesting approach. Maybe this is, daptomycin could be considered or dalbovansin, interhococcus species, ampicillin plus ceftriaxone. This has become a standard approach for ampicillin susceptible, for ampicillin resistant, hycoplanin or linazolid, monotherapy. And if you're dealing with grand negatives here, you have a problem, especially if it's fluoroquinolone resistance. If it's ESBL positive, usually the drug that's easiest to use would be a once-daily drug like ertapenem. But if you have ESBL, in many cases it's going to be resistant to fluoroquinolones. Many of the regimens are similar for other forms of disease, infection. So I won't go into this too much, but for example, chronic osteomyelitis, many of the same combinations, spondylomyelitis, combinations with rifampin, in many cases, combination therapy. So just be aware that there's a lot of interest in combining some of these newer drugs and combinations. But I think from a stewardship standpoint and from an evidence-based approach, we don't know for sure that these regimens are associated with improved outcomes. And of course there is potential risk for an increased adverse effects. So that's something that needs to be established. The last point I just want to make before we stop is that there is sometimes a need for suppressive antibiotic therapy. This is a highly individualized situation. Usually these are of course patients who have prosthetic joint infections, patients who have limited options for revision. They can't undergo DARE. They may have recurrent infections or they were trying to reduce the risk for amputation or for many other reasons. For example, they have a difficult to treat pathogen such as pseudomonas or Canada, or they're immunocompromised. So there are situations where suppressive antibiotic therapy may be continued for longer periods of time. Patients who generally don't benefit, this is criteria once again from Nicholas, who is Penfeld who has a lot of experience in treating these infections. A very nice review published in CID in 2024. And he suggests that people who have the benefit the most from suppressive antibiotic therapy are people who after DARE, who have major in-organ disease such as cirrhosis, end-stage renal disease or heart failure, older patients or life expectancy less than 10 years, who have a late hematogenous infection, gram negative infection that can't be treated with a fluoroquinolone, or the patient's desire is to have suppressive antimicrobial therapy and you explain the risks to them, but it's a shared informed decision-making. So our horizon for really reversing the problem and managing the infection and getting back functionality is much shorter. So in many cases, the benefits of suppressive antibiotic therapy may outweigh this. So this is always an individualized and difficult to treat decision, but if you wanna go through this through an experienced clinician's eyes, I would highly recommend this paper. So I hope you found this to be useful. This is sort of an overview of the infections and some of the most common controversies that we deal with in managing bone and joint infections. And I guess at this point, my intention is not to keep you any longer than necessary. So I'll just open this up now for any questions or comments or your experience in managing these infections. I find it hard to believe I said everything correctly. So please correct me if you have a different idea. (laughs) (pop) Or you think it's more time for a spritz than a question and answer. (laughs) Do any of you have experience using these combinations that I've talked about for treating osteomyelitis or using the longer acting glycopeptides for treating osteomyelitis? - We know that usually in Padua, they use the balancing for long acting. But in other places, no, because it's usually enough labor. - Yeah, yeah. An off-label indication. There's a lot of, interestingly, in a lot of places, like in the US, they have to establish a business plan to justify why they think using it off-label makes sense economically to establish it and use it. But I think that over time, it's certainly going to become a much more common practice. And then the question is going to be, is therapeutic drug monitoring part of it or is it unnecessary? Most of the TDM data I've seen with dabavancin has really shown that the exposures are quite good. So I don't see this, yes, there's variability in blood levels, but there's no evidence that the variability is so extreme that it's associated with toxicity or clinical failures. And the clinical response rates have been quite good so far, all the data that I've seen personally. So I think it's definitely going to be probably a future approach. - Thank you. - Okay. Well, if there aren't any other comments or questions or concerns, I am going to, once again, I'll just reiterate what I said for those of you who joined late, this is being recorded still. I'm going to place this recorded presentation on a website. I will create the website tomorrow and upload it. I'll put some of the references we discussed, some interesting reviews. I'll even put some links to some podcasts if you're interested on the discuss these topics. The other question we have to decide is the next lecture. I know we're getting into summer vacations and doing a lecture at night, this time of night's not always nice, but if we can maybe try to establish one more date to do one more lecture, we talk about infections in leukemic patients, we can maybe do one more lecture and then I'll put all the materials up and then I'll contact you individually after probably we come back in the fall to do a quick oral exam so we can check this box in your training. Okay, does that sound good? - Yes, yes, yes. That's okay. - Okay, fantastic. Well, thank you for your patience and taking time out to discuss and listen to discussion on osteomyelitis and bone and joint infections. - Thank you. - And I hope to meet you in person sometime in the near future. (speaking in foreign language) (laughing)