Cutibacterium Acnes in Spine Pathology: Pathophysiology, Diagnosis, and Management

Review Article Cutibacterium acnes in Spine Pathology: Pathophysiology, Diagnosis, and Management

Abstract Jad G. Khalil, MD Cutibacterium acnes, long thought to be skin flora of pathological Sapan D. Gandhi, MD insignificance, has seen a surge in interest for its role in spine pathology. C acnes has been identified as a pathogen in native spine Daniel K. Park, MD infection and osteomyelitis, which has implications in the Jeffrey S. Fischgrund, MD management compared with more commonly recognized pathogens. In addition, It has also been recognized as a pathogen in postoperative and implant-associated infections. Some evidence exists pointing to C acnes as an unrecognized source of otherwise aseptic pseudarthrosis. Recently, it is hypothesized that low virulent organisms, in particular C acnes, may play a role in degenerative disk disease and the development of Modic end plate changes found in MRI. To this end, controversial implications exist in terms of the use of antibiotics to treat certain patients in the setting of degenerative disk disease. C acnes continues to remain an expanding area of interest in spine pathology, with important implications for the treating spine surgeon.

utibacterium acnes, long thought in spine pathology has the potential Cto be skin flora of pathological to change the way these conditions insignificance, has seen a surge in in- are treated. This article reviews the terest for its role in human disease. current understanding of the role of Studies have linked Cacnesto sys- C acnes in spine pathology, with temic diseases, such as sarcoidosis, and particular emphasis on the evolving organ-specific diseases, such as benign potential role of C acnes in degen- From the Department of 1 Orthopaedics, Beaumont Health prostatic hypertrophy. C acnes has erative spine conditions. System, Royal Oak, MI. garnered attention in orthopaedic surgery because of its strong, and None of the following authors or any immediate family member has often problematic, link to peri- Microbiology received anything of value from or has prosthetic joint infection, particu- stock or stock options held in a larly shoulder arthroplasty.2 In the C acnes is an anaerobic, nonspore commercial company or institution 1 related directly or indirectly to the realm of spine pathology, C acnes forming, Gram-positive rod. Not subject of this article: Dr. Khalil, has similarly been linked to both only does Cacneslive in the super- Dr. Gandhi, Dr. Park, and native infections and postoperative ficial skin but also it is present in high Dr. Fischgrund. implant-associated infections. More numbers in hair follicles and seba- J Am Acad Orthop Surg 2019;27: recently, there has been an increase ceous glands deeper in the skin. C e633-e640 in interest in recognizing the poten- acnes is concentrated in the back and DOI: 10.5435/JAAOS-D-17-00698 tial role of C acnes and degenerative neck, axilla, and chest wall, possibly spinal conditions, particularly disk explaining its involvement in spine Copyright 2018 by the American Academy of Orthopaedic Surgeons. herniation and degenerative disk and shoulder pathology. Males tend disease. The evolving role of C acnes to have higher concentrations of C

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Table 1 Common Spondylodiscitis Secondary to High-virulent Organisms Versus Cutibacterium acnes Spondylodiscitis Factors Common spondylodiscitis Cutibacterium acnes spondylodiscitis

Back pain Significant Mild to moderate, rarely significant Systemic symptoms Present Often absent ESR/CRP Significantly elevated Slightly elevated or normal History of spine procedure Not necessary Almost always Diagnosis MRI with contrast sufficient, MRI can be similar to degenerative changes, cultures for antibiotic treatment require tissue culture Positive cultures for diagnosis 1 2 Nonsurgical management Absence of organized abscess or Absence of organized abscess or neurologic neurologic deficit deficit Surgical management Failure of IV treatment, neurologic Failure of IV treatment, neurologic deficit, deficit, organized abscess organized abscess

CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, IV = intravenous

acnes compared with females.3 In of infection. Up to 97% of patients would be missed if only anaerobic addition, the location and concentra- diagnosed with discitis have a his- culture media are followed.12 tion of C acnes can vary based on pH, tory of spine surgery or procedure, Given the rare nature of native spine temperature, moisture, and sebum such as lumbar diskectomy or epi- infections secondary to Cacnes,no content of the skin.4 dural catheter placement for anal- clear consensus on treatment exists. gesia, but the history may be in the In the absence of abscess formation or remote past.7-10 The average delay neurologic compromise, a course of Native or Non–implant- between the index procedure and antibiotic treatment may be reason- associated Infections development of spondylodiscitis is able.6 However, most patients with 34 months.11 Unlike spondylodisci- organized abscess or neurologic Although often considered a low- tis caused by more familiar micro- symptoms will require surgical de- virulent organism, C acnes has been organism, spondylodiscitis caused by compression and débridement.6,11 rarely associated with native infec- C acnes may result in normal or only Whenever possible, placement of tious conditions of the spine. In a slightly elevated erythrocyte sedimen- hardware in the setting of infection series of patients with pyogenic oste- tation rate (ESR) and C-reactive pro- should be avoided because cases of omyelitis, Carragee5 reported low- tein (CRP).6 Confirmatory diagnosis relapsed infection has been associ- virulent organism as the primary of spondylodiscitis requires advanced ated with hardware placement at the infectious species in 41 of 111 pa- imaging with MRI or bone scan if time of débridement.6 In general, good tients (36.9%). Specifically, C acnes there are contraindications to MRI. outcomes can be expected in patients was found as the primary infectious Most importantly, microbiological with native C acnes infection, given agent in 4% of patients. Kowalski proof of C acnes infection is required. appropriate diagnosis and adequate et al6 reported a series of nine pa- Given the possibility of contaminant, a treatment.6 In general, patients with tients who were diagnosed with C single positive culture may lead to native C acnes discitis can be treated acnes vertebral osteomyelitis via two overtreatment of patients.6 Thus, the with 6 weeks of parenteral beta- separate positive culture results. Two authors suggest initiating treatment lactam, such as ceftriaxone.6 of these patients had relapse of their of non–implant-associated Cacnes infection at 2.5 and 4 years after the infection if two or more cultures that initial treatment. have been followed for an appropriate Implant-associated Diagnosis of native spondylodisci- amount of time are positive. In gen- Infection tis and/or osteomyelitis in the absence eral, cultures for Cacnesshould be of spinal implants is often a chal- grown on both aerobic and anaerobic Postoperative infection after spine lenging diagnosis to make (Table 1). culture media for a minimum of surgery, particularly in the setting Patients may complain of only axial 13 days to maximize isolation.12 of implant placement, can be a dev- low back pain without systemic signs However, 29.4% of C acnes diagnoses astating complication that leads to e634 Journal of the American Academy of Orthopaedic Surgeons

Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited. Jad G. Khalil, MD, et al additional surgeries and sometimes history of spine surgery and hard- associated infections, outcomes of poor clinical outcomes. Infection can ware placement, even after a long implant-associated infections second- occureitherintheearlyorinthelate symptom-free period, should prompt ary to Cacnesare generally poor postoperative period, based on suspicion for indolent infection. Level compared with infection secondary to whether the infection presents before of ESR and CRP may be normal or other organisms.18 Patients who are or after 4 weeks postoperatively.13 only slightly elevated, and the absence being treated for deformity may ex- Latent postoperative infections are a of elevated inflammatory markers perience less correction compared subset that may present years after should not rule out infection.17 with their noninfected counterparts.19 the index surgery.13 Although Additionally, the surgical incision Staphylococcus aureus is the most may not show any signs of erythema common organism for implant- or breakdown. Radiographic evi- “Aseptic” Pseudarthrosis associated infection within 1 year dence of “halo” formation around after surgery, C acnes and other screws, osteolysis, or evidence of The cause of pseudarthrosis after spine skin flora may be responsible for a pseudarthrosis of the fusion mass may surgery is often related to patient fac- significant portion of latent be the only objective sign of infection tors (tobacco use, diabetes, and oth- infections.14,15 in the absence of other systemic signs ers),surgicaltechnique (inadequate LaGreca et al14 retrospectively re- or laboratory signs. graft placement or poor fusion bed viewed 112 patients who required A diagnosis of postoperative implant- preparation), or mechanical factor surgical débridement for infection associated C acnes infection generally (hardware failure, inadequate stabili- after instrumented spinal fusion and requires two positive periprosthetic zation). Cases of symptomatic pseud- found that C acnes was the most and hardware cultures. As with native arthrosis that warrant revision surgery common microbial species in in- Cacnesinfection, both aerobic and should undergo an infectious workup fections that presented more than 1 anaerobic culture media should be with complete blood counts, ESR, and year after the index procedure. Far- followed for a minimum of 13 days. CRP because deep infection can result ley et al15 compared 20 patients with Two or more positive cultures should in pseudarthrosis. In cases where surgical site infections after pediatric prompt surgical management. Anti- infection is not suspected clinically or scoliosis surgery with 50 patients biotics alone will likely not cure an has been ruled out with laboratory without postoperative infection. They infection in the presence of hardware. tests, the diagnosis of “aseptic pseud- identified skin flora, including C In a subset of patients who cannot arthrosis” is made, with the assump- acnes, as a major causative of infec- tolerate surgery, suppressive anti- tion that a patient or technical factor is tion and recommended adjustment of biotics may be a reasonable option. likely responsible. However, because perioperative antibiotic regimen to Surgical management consists of of its low virulence and often indolent include adequate coverage of these open exploration of the previous presentation, C acnes has been pro- bacteria. Shiono et al16 conducted a surgical site and fusion mass if posed as a possible causative agent in prospective clinical study examining applicable, removal of hardware if some presumed aseptic cases, consid- wound contamination during poste- possible, and extensive débridement. ering that the ongoing infection may rior spinal deformity surgery, ob- No clear consensus on treatment suppress local osteogenesis. taining cultures from the lamina just exists. Patients should be treated with Shifflettetal20 conducted a retro- after exposure, just after instrumen- parenteral antibiotics for at least spective review of 578 revision sur- tation placement, and just before 6 weeks, with some reports recom- geries performed for presumed aseptic closure. They found that wound mending 10 to 12 weeks.11 Parenteral pseudarthrosis and found that pseud- contamination was the highest just beta-lactam is typically the antibiotic arthrosis was the most common before closure, and the most frequent of choice, unless it is a penicillin- diagnosis for which intraoperative species cultured was C acnes. Their resistant strain of C acnes.6,11 Life- cultures were obtained (49.1%). In findings showed that wound con- long suppression antibiotics should addition, pseudarthrosis was the tamination at the time of surgery is be considered in patients who are most common reason in which in- mostly from the patient’s skin, and unable to tolerate surgical inter- traoperative cultures were unex- the probability of infection increases as vention, or in those who fail more pectedly positive (55.6%). C acnes the length of surgical time increased. than one revision surgery with ap- was cultured in 54.2% of patients Similar to native infections second- propriate antibiotic therapy. Close with the primary diagnosis of aseptic ary to C acnes, implant-associated follow-up is needed to ensure that pseudarthrosis. Given the high rate infections may have an indolent patients do not have loss of defor- of positive cultures in these cases, clinical picture. Back pain with a mity correction. Unlike non–implant- some authors recommend that cultures

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Figure 1 stood, it has been classically thought of as a premature onset of age-related changes in the intervertebral disk, including decreased water content, altered enzyme activity, and decreased end plate permeability.21 Many etiologies, including genetic, biome- chanical, traumatic, and vascular etiologies, have been proposed.21 These are most likely the predominant mechanisms of degeneration of the intervertebral disk. However, until recently, the role of potential infectious mediators in the development of disk degeneration had not been considered. Some authors have speculated that the role of C acnes is analogous to that of Helicobacter pylori in peptic ulcer disease.22 Although there is no clear evidence to support this dramatic link, the role of C acnes in degenerative disk disease is an expanding area of interest in the literature.

Modic Changes Modic changes refer to MRI findings in the end plates adjacent to degenerative disks.23 They were first de- scribed by Modic and can be either type 1 or type 2 changes. Type 1 changes refer to decreased signal intensity on T1-weighted images and increased signal intensity on T2- weighted images in the end plates and vertebral bodies adjacent to the degenerative disk. Type 2 changes refer to increased signal intensity on T1-weighted images and isointense or slightly increased signal intensity 23 Workup and management of pseudarthrosis. CBC = complete blood count. in T2-weighted images. The most likely pathophysiology related to these changes is end plate fissuring should be routinely taken and followed cultures grow positive. Our suggested and breakdown created by disk defor an adequate amount of time to rule approach for the treatment of pseud- generation, and associated reactive out C acnes infection, on revision sur- arthrosis is outlined in Figure 1. inflammation and edema.23 gery performed for pseudarthrosis.20 Some controversy exists in relation to Cases of pseudarthrosis complicated Modic type 1 changes. These changes with C acnes infection can be consid- Degenerative Disk Disease are consistent with edema, can some- ered as aseptic pseudarthrosis at the times have a very similar appearance to time of surgical intervention and trea- Although the exact pathophysiology spondylodiscitis, and thus may be sec- ted with antibiotics postoperatively if of disk degeneration is poorly under- ondary to infection by a low-virulent e636 Journal of the American Academy of Orthopaedic Surgeons

Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited. Jad G. Khalil, MD, et al organism, such as C acnes. In general, prospective study of 120 patients who tion is a potential explanation for their 4.2% of patients with type 1 Modic underwent lumbar diskectomy, ana- findings, as they did not have a con- changes, but without other overt signs lyzing excised disk material for C taminant controlintheirstudy, of infection, may develop pyogenic acnes using polymerase chain reaction inflammation caused by these organ- spondylodiscitis at 2 years of follow- (PCR) to detect the 16S recombinant isms may play a role in the initiation of up.24 In addition, patients with low DNA (rDNA) specific for C acnes, the degenerative cascade. Agarwal back pain and Modic type 1 changes first used by Fritzell et al.30,31 They et al reviewed a case series of 52 have evidence of systemic inflamma- found that most patients with positive immunocompetent patients undergo- tion that is not present or present Cacnesfindings had evidence of ing single-level lumbar diskectomy to a lower degree in patients without Modic 1 changes on their MRI. In and found that disk cultures were Modic change or Modic 2 changes, contrast, Wedderkopp et al32 obtained positive in 19.2% of patients (n = 10), respectively.25 vertebral body biopsiesin24patients of whom 7 patients had positive C Dudlietal26 investigated the biologic with evidence of Modic 1 changes on acnes culture. Zhou et al36 conducted plausibility of the ability of Cacnesto MRI and found that none of their a study of 46 patients undergoing cause type 1 Modic changes in a rat cultures grew Cacnes. Arndt et al and lumbar diskectomy. They used PCR to model. C acnes from a symptomatic Rigal et al also did not find evidence to detect C acnes–specific 16S rDNA and humanL4-5diskwithevidenceof support a connection between Cacnes muscle biopsy as controls and found Modic 1 changes on MRI was isolated and Modic 1 changes.33,34 At this that 23.9% of disk PCRs had positive andinoculatedintorattaildisks.This point, although C acnes provides an findings for Cacnes. In addition, C was found to lead to an upregulation interesting etiology for Modic 1 acnes was more likely to be found in of IL-1 and IL-6 within 3 days. Evi- changes, the connection between this disk herniations with an annular tear dence of Modic 1 changes was ob- MRI finding and indolent infection is compared with those without an served at 2 weeks postinoculation. not absolutely clear. annular tear. Rao et al37 reported a Chen et al27 examined the effect of similar rate of 19.6% positive cultures disk inoculation with Cacnescom- from 168 patients who underwent pared with S. aureus species in a rabbit Disk Herniation anterior cervical, anterior lumbar, model and found that C acnes inoc- Stirling et al35 were among the first to posterior cervical, or posterior lumbar ulation resulted in only moderate disk describe a potential relationship be- spine. Although their findings confirm degeneration and Modic 1 changes on tween low-virulent organisms, chronic previous reports, Rao et al did not MRI, compared with more classic infection, and degenerative conditions report a specific contaminant control. MRI findings of pyogenic spondylo- of the spine. They cultured disk Evidence incriminating C acnes in discitis seen with S. aureus inocula- material from 36 patients undergoing the degenerative cascade was also tion. Shan et al28 examined the effects lumbar microdiskectomy and found found at preclinical and translational of Cacnesinoculation in lumbar disks that 19 patients (53%) had positive levels. Chen et al27 examined the in a rabbit model and found that C cultures after long-term incubation, of effect of disk inoculation with C Acnes can survive within the end plate which 16 (84% of positive cultures) acnes compared with S. aureus spe- region of the intervertebral disk and grew C acnes. Since the publication of cies in a rabbit model and found that cause an inflammatory reaction simi- their findings, the role of low-virulent although S. aureus was associated lartoModic1changesonMRI. organisms, most often Cacnes,has with septic discitis as expected with Clinical studies have shown mixed remained a point of contention, with high-virulent organisms, C acnes results regarding a correlation between studies reporting conflicting results. inoculation resulted in moderate disk Modic 1 findings on MRI and the Several clinical and preclinical studies degeneration and end plate rupture. presence bacteria. Albert et al29 have supported the notion that C acnes Rajasekaran et al22 performed a found a relationship between anaero- may be an instigator in the develop- proteomic and 16S rDNA analyses bic bacteria isolated in herniated disk ment of degenerative disk pathology. of disk tissues obtained from 22 material in patients undergoing lum- Arndtetal33 conducted a prospective patients undergoing lumbar spine bar diskectomy and new Modic type 1 study culturing the disks of 83 patients surgery. Using a combination of liq- changes. They asserted that disk her- undergoing or were to undergo lum- uid chromatography-tandem mass niations may provide opportunity for bar disk replacement. They found that spectrometry for protein analysis low-virulence organisms to enter the 40 of 83 patients had a positive cul- and PCR for 16S rDNA analysis, disk space and subsequently cause ture, including 18 patients with posi- they found evidence of not only the phenomenon of Modic type 1 tive C acnes cultures. They admit that bacteria-specific rDNA but also changes. Aghazadeh et al conducted a although intraoperative contamina- host pathogen–specific proteins

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Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited. Cutibacterium acnes in Spine Pathology evident of low-grade infection. Li conditions of spine opens the door to that although some studies provide a et al38 suggested that although the the potential of treatment with anti- compelling case for a contributory intervertebral disk is a suitable en- biotics for chronic low back pain.40 role of Cacnesin some degenerative vironment for C acnes growth, Albert et al41 hypothesized that processes of the spine, there is insuf- however, it is doubtful for C acnes to chronic low back pain and type 1 ficient evidence currently to change be able to inoculate the disk by Modic changes on MRI after a pre- our current understanding of the means of bacteremia. vious disk herniation is related to a predominant pathophysiology or Other authors have refuted these low-virulent organism infection.40,41 management of degenerative disk findings and the role of C acnes and They conducted a double-blinded, disease. However, unlike the degen- other low-virulent organisms in the randomized, controlled trial in 162 erative spine setting, we do think development of degenerative disk patients with persistent back pain that in patients with previous spine disease. Carricajo et al39 conducted and type 1 Modic changes after a surgery, indolent infection should be a prospective study in 54 patients previous disk herniation comparing on the clinician’s differential. undergoing surgery for lumbar disk the efficacy of 100 days of antibiotics herniation to evaluate the presence (ie, amoxicillin-clavulanate) against of C acnes in degenerative disks. placebo. They found that patients in Conclusion Along with obtaining cultures from the antibiotic group did significantly the disks, Carricajo et al obtained better than those in the placebo for The role of Cacneshas grown from a control samples from surrounding all primary and secondary outcome nonvirulent organism that is part of ligamentum flavum and muscle, air measures. The publication of these skin flora to a potential major player samples, and laminar flow control findings was met with significant in spine pathology, incriminated in samples. They found positive disk controversy, with some authors native and implant-related infections, cultures in only 2 of 54 patients, in pointing out critical issues with as well as to disk degeneration. Given whom control samples from sur- researcher conflicts of interest and its indolent clinical picture, diagnosis rounding ligamentum flavum and certain aspects of study methodol- of infection secondary to Cacnescan muscle was also positive. They also ogy and data analysis.42,43 To our be difficult. Cacnesin nonimplant or found positive samples in control knowledge, no other study has been native spondylodiscitis is a rare ligamentum and muscle samples, air able to replicate the findings of Al- infection that can often be missed samples, and laminar flow samples bert and colleagues, nor have anti- or underdiagnosed. It is generally in patients who did not have positive biotics been tried as a primary associated with previous spine pro- disk samples; they strongly suggested treatment modality in patients other cedures or surgery. Often, it has good that positive findings in other reports than the narrow subset of those with outcomes with appropriate treat- may be because of contaminants. new Modic 1 changes after a previous ment. Postoperative Cacnesinfection Rigal et al34 reported a 1.6% (n = 6) disk herniation. We do not routinely in the setting of spinal hardware is positive culture rate in 313 patients use antibiotics in this patient pop- also an indolent process that may not who underwent video-assisted ante- ulation at our institution. have the usual systemic or laboratory rior lumbar interbody fusion or signs of infection; it may present anterior lumbar disk replacement; many years after the index procedure. no cases of delayed or secondary Limitations The treating surgeon should have a infection was reported. Unlike the One significant limitation in the find- high index of suspicion for Cacnes posterior approach, Rigal et al were ings by many of the studies reporting infection in the setting of sudden able to obtain biopsy samples with- positive Cacnescultures in patients worsening of back pain after a long out any skin contact; they suggested with degenerative disk disease is the symptom-free period, because it is the that the anterior laparoscopic ap- inherent potential for contamination most common cause of infection proach allowed a relatively low con- while obtaining cultures. Some stud- more than 1 year after the index tamination rate. ies have attempted to circumvent this procedure. In addition, there may limitation by focusing on proteomic be a role for cultures during surgery analyses rather than strict culture for aseptic pseudarthrosis because Antibiotics in the Treatment results.22 In addition, there has been a some of these cases may be related to of Low Back Pain lack of standardization of obtaining C acnes infection. Most controver- The possibility of a connection be- cultures in many studies attempting sial is the role of C acnes in the tween infection secondary to low- to link disk herniation and Cacnes degenerative processes of the spine. virulent organisms and degenerative infection. At this point, we suggest Conflicting results and controversy e638 Journal of the American Academy of Orthopaedic Surgeons

Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited. Jad G. Khalil, MD, et al regarding the role of C acnes in disk review of the literature. Clin Microbiol chronic low back pain with vertebral end- Infect 2010;16:353-358. plate Modic signal changes. Arthritis herniation, Modic 1 changes on Rheum 2007;57:1311-1315. MRI, and the role of antibiotics in 12. Butler-Wu SM, Burns EM, Pottinger PS, et al: Optimization of periprosthetic culture 26. Dudli S, Liebenberg E, Magnitsky S, Miller the treatment of low back pain has for diagnosis of Propionibacterium acnes S, Demir-Deviren S, Lotz JC: stimulated more research in the area. prosthetic joint infection. J Clin Microbiol Propionibacterium acnes infected 2011;49:2490-2495. intervertebral discs cause vertebral bone marrow lesions consistent with Modic 13. Sasso RC, Garrido BJ: Postoperative spinal changes. J Orthop Res 2016;34:1447-1455. References wound infections. 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