Clinical Review (insufficient quality of evidence to enable a Clear Recommendation):
Observational studies indicate that imaging and inflammatory biomarkers are not diagnostically accurate for osteomyelitis underlying a pressure ulcer and we do not recommend their routine use for this purpose. Antibiotics have not been shown to be of benefit, and may be of harm, in the absence of surgical wound closure, but osteomyelitis may increase the risk of surgical flap failure.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) Therefore, it may be preferable to avoid the routine use of antibiotic therapy for osteomyelitis underlying a pressure ulcer unless deep bone biopsy confirms osteomyelitis and surgical wound closure is planned, or the patient has accompanying sepsis syndrome or local soft tissue infection. Irrespective of antibiotic use, a multi-modal therapeutic approach includes nutritional optimization, wound debridement and care, pressure off-loading, and psychosocial management.
No RCTs have been published that define optimal diagnostic or management strategies for osteomyelitis underlying a pressure ulcer.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) However, observational studies of various designs, sizes, and quality have been published that evaluate aspects of the disease.
Histopathological analysis and bone culture
Bone biopsy for histopathologic analysis remains the gold standard for confirming the diagnosis of osteomyelitis. Surprisingly, despite classical teaching that exposed bone signifies osteomyelitis is present by definition, when exposed bone has been biopsied in published studies, osteomyelitis was present on histopathology in fewer than half of cases.(Turk, Tsokos et al. 2003, Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) Rather, in many instances, what was identified on biopsy was fibrotic bony remodeling with medullary edema, which may be indistinguishable from osteomyelitis on imaging studies.(Sugarman, Hawes et al. 1983, Darouiche, Landon et al. 1994, Turk, Tsokos et al. 2003)
For example, Türk et al. examined histologic autopsy specimens of 28 patients with advanced-grade pressure ulcers, specifically those with visible bone.(Turk, Tsokos et al. 2003) In 15 cases, osteomyelitis was not detectable histologically. In the remaining 13 cases with osteomyelitis, disease was generally focal and superficial. Osteomyelitis has been described to be absent frequently even in bone exposed for months to years, and no correlation has been found between the duration of bone exposure and the risk of osteomyelitis.(Sugarman, Hawes et al. 1983, Darouiche, Landon et al. 1994, Turk, Tsokos et al. 2003) As bony remodeling rather than osteomyelitis was described the majority of instances of exposed bone,(Sugarman, Hawes et al. 1983, Darouiche, Landon et al. 1994, Turk, Tsokos et al. 2003) perhaps it is not surprising that alternative methods of diagnostic testing have been found to be highly inaccurate at detecting osteomyelitis underlying pressure ulcers.(Wong, Holtom et al. 2019)
Skin and open ulcers are invariably colonized by bacteria, so superficial cultures are expected to yield bacterial growth. Thus, wound swabs or cultures taken from superficially debrided material are not helpful in establishing diagnosis, as organisms recovered are often colonizers and not true pathogens.(Chicco, Singh et al. 2020, Russell, Tsang et al. 2020) Indeed, surface cultures are inaccurate at determining whether infection is present in deeper bone, or, if present, at predicting which bacteria are etiologic for osteomyelitis in deeper bone.(Chicco, Singh et al. 2020, Russell, Tsang et al. 2020) One systematic review of four studies compared the accuracy of microbial culture to bone histopathology for the diagnosis of osteomyelitis underlying pelvic pressure ulcers.(Chicco, Singh et al. 2020) In the four studies, tissue and bone cultures were reported, with the latter obtained by percutaneous or surgical bone biopsy.(Sugarman, Hawes et al. 1983, Thornhill-Joynes, Gonzales et al. 1986, Darouiche, Landon et al. 1994, Brunel, Lamy et al. 2016) However, in three of the studies surface material was not debrided prior to the needle biopsy of bone;(Sugarman, Hawes et al. 1983, Thornhill-Joynes, Gonzales et al. 1986, Darouiche, Landon et al. 1994) in the remaining study, surface material was debrided before a surgical biopsy of bone was obtained.(Brunel, Lamy et al. 2016) The diagnostic performance of microbial culture varied widely across the studies, with sensitivities of 18% to 100% and specificities of 43% to 100%, likely reflecting different definitions of commensal vs. pathological organisms and/or different methodologies of obtaining cultures.
Thus, rather than having diagnostic utility, the primary purpose of bone cultures is to guide antibiotic selection for therapeutic purposes. As such, we do not recommend routinely obtaining bone cultures unless they are from a deep bone biopsy that confirms osteomyelitis and there is a plan to definitively treat the infection with culture-driven antibiotics (see below). If bone cultures are obtained, it is logical to collect them after debriding surface material to decrease the burden of confounding bacterial colonizers.
Blood biomarkers and acute phase reactants
Soft tissue edema around exposed bone can trigger low level inflammation, and one study found typical biomarkers, such as leukocytosis, ESR, and CRP, to be neither sensitive nor specific for distinguishing the presence or absence of osteomyelitis underneath pressure ulcers.(Thornhill-Joynes, Gonzales et al. 1986) In the absence of any studies indicating that these tests are accurate for diagnosing osteomyelitis underlying pressure ulcers (as for other types of osteomyelitis, see Section 1), we do not recommend routinely ordering biomarkers for this purpose.
Unfortunately, imaging studies are also not accurate for diagnosing osteomyelitis beneath a pressure ulcer, likely because they cannot distinguish bony remodeling from infectious osteomyelitis.(McCarthy, Hartmann et al. 2017, Wong, Holtom et al. 2019, Chicco, Singh et al. 2020, Crespo, Stevens et al. 2020) Specifically, plain X-rays, CT scans, and nuclear medicine studies had sensitivities of 60% or less when compared to bone biopsies in observational studies.(Lewis, Bailey et al. 1988, Merine, Fishman et al. 1988, Larson, Gilstrap et al. 2011, Chicco, Singh et al. 2020) Specificities of these tests varied widely in published studies (ranging from 11% to 100%). While specificities were higher in studies comparing these tests to clinical diagnosis,(Chicco, Singh et al. 2020) clinical diagnosis is known to be inaccurate,(Chicco, Singh et al. 2020) and hence specificities of imaging tests compared to anything other than bone biopsy are difficult to interpret. The finding of destroyed bone on imaging is likely more specific for osteomyelitis, but is a very late finding, and thus uncommon, which may also account for variations in the specificity in the published observational studies.
Given these limitations, we do not recommend routinely obtaining such imaging modalities for diagnosing osteomyelitis underlying pressure ulcers. If bony destruction is incidentally observed on plain radiography or CT scan obtained for other reasons, it may indeed strongly suggest the presence of osteomyelitis. Such information should then be incorporated into an overall management strategy dependent primarily on whether there is a plan to surgically close the wound (see below).
In several studies, MRI had a sensitivity in excess of 80%-90% for detecting osteomyelitis underlying pressure ulcers.(Huang, Schweitzer et al. 1998, Brunel, Lamy et al. 2016, McCarthy, Hartmann et al. 2017) However, its specificity was very poor (17%-22%) compared to the reference standard of bone biopsy.(Brunel, Lamy et al. 2016, McCarthy, Hartmann et al. 2017, Chicco, Singh et al. 2020) Again, this poor specificity is likely due to inability of MRI to distinguish osteomyelitis from the reactive remodeling that occurs in exposed bone. Therefore, despite having a relatively high sensitivity overall, due to poor specificity, MRIs have low positive and negative likelihood ratios (≤2), which are not adequate to meaningfully shift pre-test probability of osteomyelitis underlying a pressure ulcer in most patients.
Summary of diagnostic approach
A critical point is that the diagnosis of osteomyelitis underlying a pressure ulcer is only important to make if such a diagnosis will alter the management plan for the patient.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) As discussed below, absent the intent to surgically debride and definitely close an open wound, it is not clear that treatment of osteomyelitis with antibiotics improves the long-term outcomes of pressure ulcers (but evidence suggests antibiotic therapy may perversely worsen outcomes without closing the wound). A standard wound care and debridement management plan should be implemented irrespective of the presence of osteomyelitis. Thus, it may be futile to order diagnostic testing outside the setting of a plan to close the wound, as detecting osteomyelitis (even if one could accurately do so) would not alter the clinical management plan.
In summary, based on the limited retrospective data available, we do not recommend the routine use of biomarkers (including WBC count, ESR, CRP) or X-rays, CT or nuclear medicine imaging, or surface cultures to diagnose osteomyelitis underlying pressure ulcers. MRIs may only be useful in planning for definitive surgical debridement and wound closure as part of a comprehensive management plan, as delineated below. While it may seem as though a negative MRI could suggest a lack of osteomyelitis, obviating the need for more invasive testing, with a negative likelihood ratio of ≤2, a negative MRI shifts the published pre-test probability of approximately 50% of osteomyelitis for those with stage-4 pressure ulcers to a post-test probability of approximately 33%, which is inadequate to exclude the diagnosis. Even with a pre-test probability of only 25%, a negative MRI would shift the post-test probability to 17%, still inadequate to exclude the diagnosis.
The only diagnostic test that is of demonstrated value for osteomyelitis underlying a pressure ulcer is bone biopsy. Furthermore, in the absence of a plan to provide definitive wound closure, we do not recommend a bone biopsy to establish a diagnosis of osteomyelitis, as it is not clear how such a diagnosis would alter management. In contrast, if there is an intent to administer definitive therapy, including surgical wound closure, it is reasonable to consider surgical debridement of the wound, enabling deep bone biopsy for histopathology as the primary diagnostic modality to detect osteomyelitis. In this case, bone biopsy cultures should also be sent to enable targeting of antimicrobial therapy as part of the comprehensive management plan.
Two systematic reviews of pressure-ulcer associated osteomyelitis, published in infectious diseases and orthopedic surgery journals, failed to identify any literature demonstrating a therapeutic benefit of antibiotics alone for osteomyelitis underlying a pressure ulcer; antibiotics had a positive effect only when administered in conjunction with definitive interventions to debride and close the wound.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) Antimicrobial agents may be rationally administered to treat an acute soft tissue infection around the wound, and in this case should be administered for only a brief period of time (e.g., ≤ 1 week) to treat an acute bacterial skin and/or skin structure infection, or sepsis syndrome, rather than an osteomyelitis. Exposure of patients to antibiotics for longer durations without surgical debridement and wound closure could increase their risk of harm (e.g., adverse events), as well as promote the emergence of antibiotic-resistant pathogens that colonize the wound, creating risk for future antibiotic-resistant super-infections.(Wong, Holtom et al. 2019)
Indeed, in multiple observational studies of both adults and children, infectious or wound healing outcomes were not influenced by antibiotic administration (including route or duration) or the presence of osteomyelitis, particularly without surgical wound closure.(Sugarman, Hawes et al. 1983, Goodman, Cohen et al. 1999, Marriott and Rubayi 2008, Larson, Gilstrap et al. 2011, Larson, Hudak et al. 2012, Jugun, Richard et al. 2016, Firriolo, Ganske et al. 2018, Russell, Tsang et al. 2020) However, prolonged antibiotic administration (e.g., 6 weeks), and failure to address pressure off-loading, were associated with increased harm, including more frequent wound breakdown, ulcer recurrence, and longer hospitalization.(Marriott and Rubayi 2008, Larson, Hudak et al. 2012, Firriolo, Ganske et al. 2018)
Conversely, multiple observational studies of both adults and children have found substantially better wound and flap healing outcomes of osteomyelitis underlying a pressure ulcer when managed via a comprehensive plan including medical, psychosocial, and surgical approaches.(Cunha 2002, Marriott and Rubayi 2008, Larson, Gilstrap et al. 2011, Larson, Hudak et al. 2012, Bamba, Madden et al. 2017, Dudareva, Ferguson et al. 2017, Firriolo, Ganske et al. 2018, Russell, Tsang et al. 2020) Such plans have included surgical debridement to the level of healthy, viable tissue, obtaining deep cultures intraoperatively to guide subsequent antimicrobial therapy, definitive surgical wound closure, and psychosocial/behavioral interventions to alter pressure dynamics to prevent reopening of the wound and/or failure of the flap.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) Of note, in one of the largest observational studies of wound closure by flap (n = 276 patients), multivariate analysis found that low body mass index (likely reflective of malnutrition), smoking, ischial pressure ulcers (vs. other body sites), and presence of osteomyelitis in the wound before flapping predicted wound dehiscence and/or flap failure/ulcer recurrence.(Bamba, Madden et al. 2017) For pressure ulcers near the perineum or in locations frequently contaminated by stool, small observational studies have shown that performing an elective colostomy for fecal diversion is associated with decreased ulcer recurrence rate and need for subsequent operations, leading to an improved patient quality of life.(de la Fuente, Levin et al. 2003, Cooper, Bonne Lee et al. 2019) Thus, risk factors should be considered when optimizing patients for definitive surgical wound closure.
Barring surgical wound closure, no data demonstrate that the presence of osteomyelitis underlying a pressure ulcer predicts a change in likelihood of ulcer healing or recurrence. Even the finding of a positive intraoperative bone culture did not alter the future risk of flap failure in one observational study.(McCarthy, Hartmann et al. 2017) Nor do data demonstrate that administration of antibiotics in this setting, or giving longer courses of antibiotics or IV instead of orally, improves the healing or reduces recurrence of ulcers in this setting. However, as mentioned, several studies have found that giving antibiotics, and longer courses of them, is associated with harm in the absence of surgical closure of the wound, including increased wound breakdown.(Marriott and Rubayi 2008, Firriolo, Ganske et al. 2018)
Thus, in the absence of evidence for a therapeutic benefit and with data demonstrating potential harm, we do not recommend routinely administering antibiotics as a treatment for osteomyelitis underlying a pressure ulcer without an intent to both surgically debride and provide definitive wound closure. The primary therapeutic modalities for patients who are managed conservatively include local wound care, pressure offloading, and addressing the psychosocial/behavioral drivers leading to wound development and resulting in an increased risk of flap failure (e.g., malnutrition, smoking). We also do not recommend routinely ordering testing to diagnose osteomyelitis in this setting, as it will not change clinical care or management.
Furthermore, we note that even with implementation of a multi-modal, multi-disciplinary approach, there are no data to indicate that antibiotic administration reduces the risks of flap failure or recurrence of the wound/ulcer, nor are there data to guide the duration of antibiotic administration in this setting. Nevertheless, given that osteomyelitis exacerbated the risk of subsequent wound flap failure in one large retrospective study,(Bamba, Madden et al. 2017) it is reasonable to administer adjunctive antimicrobial therapy to treat biopsy-confirmed osteomyelitis in the setting of a multi-modal, multi-disciplinary approach, including definitive wound closure with curative intent.
In cases where an aggressive strategy is taken, a reasonable multi-pronged approach based on a limited number of observational studies could include: 1) nutritional optimization (to support wound healing); 2) surgical debridement down to healthy tissue followed by obtaining surgical bone Gram stain, cultures, and histopathology; 3) definitive surgical wound closure; and 4) psychosocial interventions that include pressure off-loading, education, and treatment of tobacco use disorder, depression, or other psychological factors that may impede wound healing.(Wong, Holtom et al. 2019, Crespo, Stevens et al. 2020) In situations where surgical wound closure is not intended, the same multi-pronged approach to management still applies, although obtaining bone biopsy for culture and histopathology and prescribing antibiotics should be avoided. Periodic debridement of necrotic or non-viable tissues and wound care remain important strategies for decreasing complications, including acute skin and soft tissue superinfection, even when curative approaches are not pursued.
In the setting of such a multi-faceted approach with surgical wound closure, and with confirmation of osteomyelitis on intra-operative histopathology, durations of antibiotics should generally not exceed 6 weeks (see section 7 for a full discussion on antibiotic durations for osteomyelitis), and some have suggested that courses may be as short as 2 weeks for superficial, cortical osteomyelitis.(Mader, Cripps et al. 1999, Parsons and Strauss 2004, Russell, Tsang et al. 2020) Antimicrobial therapy may be administered orally in patients who are likely to absorb the medications and for whom an oral regimen will be active against the etiologic pathogens (see section 5 for a full discussion on oral antibiotic therapy for osteomyelitis).(Spellberg and Lipsky 2012, Scarborough, Li et al. 2018) The choice of antimicrobial agent should be individualized based on patient comorbid factors, allergies, and microbial type and antimicrobial sensitivities.
We emphasize that this guideline focuses on the diagnosis and management of osteomyelitis underlying pressure ulcers specifically, not including the management of acute skin and soft tissue infections that can complicate pressure ulcers. Diagnostic studies may be indicated to assess for infectious complications of wounds aside from osteomyelitis, such as abscesses, and antimicrobial therapy is appropriate for such infections, even in the absence of multidisciplinary plans for management of potential osteomyelitis.