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Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults

Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections... Open Forum Infectious Diseases MAJOR A RTICLE Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults 1,4 1 1 5 1,2 3 1,6 Damani A. Piggott, Yvonne M. Higgins, Michael T. Melia, Brandon Ellis, Karen C. Carroll, Edward G. McFarland, and Paul G. Auwaerter 1 2 3 Division of Infectious Diseases, Division of Medical Microbiology, Department of Pathology, Division of Shoulder Surgery, Department of Orthopedic Surgery, Johns Hopkins University School 4 5 6 of Medicine, and Department of Epidemiology, Johns Hopkins University School of Public Health, Johns Hopkins Hospital Microbiology Laboratory, and Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, Baltimore, Maryland Background. Prosthetic joint infections (PJIs) significantly complicate joint arthroplasties. Propionibacterium acnes is an in- creasingly recognized PJI pathogen, yet limited clinical and therapeutic data exist. We sought to examine characteristics of P. acnes shoulder PJIs and compare surgical and nonsurgical management outcomes. Methods. A retrospective analysis of P. acnes shoulder PJIs was conducted at an academic center in Baltimore, Maryland from 2000 to 2013. Results. Of 24 cases of P. acnes shoulder PJIs, 92% were diagnosed after extended culture implementation; 42% in the delayed and 46% in the late postsurgical period. Joint pain and diminished function were the predominant presenting clinical signs. Eryth- rocyte sedimentation rate and C-reactive protein elevations occurred in 47% and 44%, respectively. All tested isolates were susceptible to β-lactams, moxifloxacin, vancomycin, and rifampin. Clindamycin resistance was identified in 6%. Of the antibiotic-only treated cases, 67% had a favorable clinical outcome compared with 71% (P = 1.0) of cases with a combined antibiotic-surgical approach. Favorable outcome with and without rifampin therapy was 73% and 60% (P = .61), respectively. Conclusions. Propionibacterium acnes PJI diagnoses increased with extended culture. Inflammatory markers were elevated in a minority of cases. Isolates maintained broad antimicrobial susceptibility. Compared to combined antibiotic-surgical approaches, an- tibiotic-only approaches were similarly successful in selected cases. Keywords. antimicrobial susceptibility; Propionibacterium acnes; prosthetic joint infection; shoulder prosthesis. Over 1 million prosthetic joints are placed in the United States region [8–10]. Initially considered an important agent in the each year. With an aging population, this number is projected pathogenesis of acne vulgaris, P. acnes has been more recently to increase 4-fold over the next 2 decades [1–3]. A notable propor- implicated in serious deep-seated postoperative and medical tion of these joints subsequently fail. Prosthetic joint infections device-related infections, particularly PJIs [11–13]. With (PJIs) have been considered to be the most serious cause of sub- improved diagnostics, including extended culture protocols, P. sequent joint failure, occurring in up to an estimated 2% of arthro- acnes has been specifically recognized as a dominant organism plasties [1, 4–6]. In addition to the clinical impact, the economic in infections involving shoulder prostheses [14–23]. Yet, there burden of PJIs is markedly high, with an estimated cost in the has been a paucity of data on the clinical and microbiologic United States approaching 1 billion dollars annually [5, 7]. characteristics of such infections. Propionibacterium acnes is a Gram-positive anaerobic bacil- Treatment of PJIs beyond the acute postoperative period has lus. It is a human commensal organism, primarily found in skin traditionally relied on an appropriate antimicrobial regimen, and superficial mucosal sites, with a predilection for piloseba- combined with a surgical approach dependent on stability of ceous follicles that exist in the upper body such as the shoulder the prosthesis, state of the periprosthetic tissue, patient comor- bidity, and characteristics of the infecting organism [1,3,6].Sur- gical options include debridement with implant retention or antibiotic spacer implantation with no subsequent arthroplasty, Received 23 September 2015; accepted 30 December 2015. Correspondence: D. A. Piggott, Division of Infectious Diseases, Johns Hopkins University a 1-stage revision with immediate reimplantation of a new pros- School of Medicine, 2213 McElderry Street, Room M141, Baltimore, MD 21205 (dpiggot1@ thesis, a 2-stage revision with reimplantation several months jhmi.edu). after prosthesis removal, permanent prosthesis removal, and Open Forum Infectious Diseases © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society amputation. Medical management options have been manifold, of America. This is an Open Access article distributed under the terms of the Creative Commons largely because antimicrobial activity against P. acnes has been Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, reported for a wide spectrum of agents [24]. However, with the provided the original work is not altered or transformed in any way, and that the work is properly increasing use of antimicrobial agents for acne vulgaris, advanc- cited. For commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ ing resistance of P. acnes isolates has been reported, particularly ofv191 P. acnes Shoulder PJIs � OFID � 1 in refractory cases of acne [25–27]. The susceptibility patterns of spot tests, and/or biochemical reagents. The extended culture P. acnes isolates implicated in deep-seated infections have been incubation protocol for P. acnes was implemented in January less well characterized. 2009, with extension from 5 to 14 days of incubation for both Medical management of PJIs without surgical intervention aerobic and anaerobic culture media. has been considered to result in poorer clinical outcomes [1, Definition 28]. Such a limited approach has typically been reserved for pa- A PJI was defined based on previously detailed criteria [1, 3, 22, tients with inoperable status [1, 6]. Occasionally, this strategy 29, 30]. A case was considered definite (1) if 2 or more culture has been considered in clinical practice for low virulence organ- specimens were positive for P. acnes with no other organisms on isms, although with limited supporting data. Propionibacterium culture or (2) if 1 culture specimen was positive for P. acnes with acnes has been considered a low virulence organism, but little no other organisms on culture and there was evidence of either data exists on the comparative advantage of combined medical joint purulence, histopathologic inflammation, or a sinus tract and surgical management to that of medical management alone communicating with the prosthesis. A case was considered for infections involving this organism. probable if 1 culture specimen was found to be positive for P. We performed a retrospective analysis to describe clinical and acnes and 1 of the following concomitant symptoms was pre- laboratory characteristics of P. acnes prosthetic shoulder joint sent:fever,constitutionalsymptoms(chills,fatigue, night infections and antimicrobial susceptibility patterns of the asso- sweats, weight loss, and anorexia), joint pain, joint swelling, ciated isolates over a 14-year period. We further describe short- joint warmth, wound drainage, or loss of range of motion. term treatment outcomes for surgical and alternative medical Cases were excluded if there was an alternative explanation approaches to the management of these infections. for these symptoms (such as gout or rheumatoid arthritis re- sponsive to therapy). There were no coexisting pathogens isolat- PATIENTS AND METHODS ed in any of the cases included in this study. Hospital Setting and Study Population Data Collection This study was conducted at the Johns Hopkins Hospital and Medical chart abstraction was performed using a standardized Clinics in Baltimore, Maryland. Linkage to the Johns Hopkins case report form to retrieve demographic, clinical, and laboratory Hospital microbiology database system was used to identify data. Demographic data included age, sex, and race. Laboratory cases from January 2000 through December 2013. Patients data included erythrocyte sedimentation rate (ESR), C-reactive aged 18 years and older with a positive P. acnes culture from protein (CRP), white blood cell (WBC) count, and percentage the shoulder joint with a prior shoulder prosthesis were identi- of neutrophils in the blood and synovial fluid. Imaging findings fied for study inclusion. This study was approved by the Johns from plain films and computerized tomography scans were re- Hopkins Institutional Review Board. corded. Laboratory and radiologic data recorded at diagnosis re- flect findings before any surgical PJI treatment. The time from Specimen Collection and Microbiologic Assessment index surgery to diagnosis was recorded as the time from the Joint fluid aspirates and operative tissue specimens were collect- last surgical procedure performed prediagnosis to the first pos- ed using standard protocols and transported to the Microbiol- itive P. acnes culture. Episodes were classified as early (<3 ogy Laboratory for processing. Joint fluid aspirates were months after surgery), delayed (3–24 months), or late (>24 transported in BD BBL Port-A-Cul vials (Becton, Dickinson months) as previously described [6]. Time to culture positivity and Company, Sparks, MD), and tissue specimens were placed was recorded as the time from joint specimen attainment to in a sterile container and transported to the Microbiology Lab- positive culture growth. oratory within 1 hour of collection. Specimens were then pro- cessed and inoculated onto standard agars, including Brucella Antimicrobial Susceptibility Patterns blood agar (Anaerobe Systems, Morgan Hill, CA), and BD The susceptibilities of P. acnes isolates were tested against a BBL Chopped Meat Broth (Becton, Dickinson and Company). range of standard antimicrobial agents. Isolates were classified Aerobic plates and chopped meat broths were incubated in 5% as susceptible as per the minimum inhibitory concentration CO at 35°C. Anaerobic plates and broth subcultures were incu- (MIC) breakpoints set by the Clinical and Laboratory Standards bated in an AS-580 anaerobe chamber (Anaerobe Systems) at Institute (CLSI): penicillin (≤0.5 µg/mL), piperacillin/tazobac- 35°C. Aerobic blood and chocolate agar plates, as well as anaer- tam (≤32/4 µg/mL), ertapenem (≤4 µg/mL), clindamycin obic Brucella and Phenyl-Ethyl-Alcohol agar plates, were held (≤2µg/mL), moxifloxacin (≤2µg/mL), and metronidazole for 14 days. Chopped meat broths were subcultured both aero- (≤8 µg/mL) or by the European Committee on Antimicrobial bically and anaerobically when turbid or terminally subcultured Susceptibility Testing (EUCAST): vancomycin (<2 µg/mL) at day 10 if clear. Organism identification was obtained using and rifampin (≤0.5 µg/mL) [11]. No CLSI or EUCAST break- the Bruker Microflex LT MALDI-TOF mass spectrometry sys- points were available for minocycline. The absolute MICs for tem (Bruker Daltonics, Billerica, MA), as well as Gram stain, isolates against minocycline are thus reported. Susceptibility 2 � OFID � Piggott et al Table 1. Demographic and Clinical Characteristics of 24 Patients With testing for penicillin was initiated in 2001; susceptibility testing Propionibacterium acnes Shoulder Prosthetic Joint Infection for clindamycin, moxifloxacin, and vancomycin was initiated in 2009; susceptibility testing for piperacillin/tazobactam, ertape- Variable No. (%) nem, and metronidazole was initiated in 2010; and susceptibil- Age, years 62 (40, 81) ity testing for rifampin was initiated in 2012. Male 19 (79) White 21 (88) Follow-Up and Treatment Outcomes Time from index surgery Antimicrobial therapeutic regimens and treatment outcomes Early (<3 mo) 3 (12) were assessed through the last recorded clinical visit. Decisions Delayed (3–24 mo) 10 (42) on therapeutic regimens were based on the clinical judgment of Late (>24 mo) 11 (46) the infectious disease and surgical specialist providers. The type, Time from specimen collection to culture positivity, days 4.5 (3–14) Clinical signs and symptoms delivery method, and duration of antimicrobial therapy were re- Joint pain 24 (100) corded. In all cases, susceptibility profiles informed drug choice. Loss of range of motion 21 (88) Concomitant use of rifampin was also per the clinical judgment Swelling 5 (21) of the infectious disease physician with consideration of patient Erythema 3 (12) tolerability. Chart abstraction did not allow for precise determi- Warmth 2 (8) Constitutional symptoms 2 (8) nation of duration of intravenous (IV) versus oral therapy. How- Wound drainage 0 (0) ever, of those who received IV antimicrobial therapy, the majority Fever 0 (0) of patients received at least a 4- to 6-week course of IV therapy Intraoperative findings prior to transition to an oral regimen. The final clinical outcome Purulence 7 (47) was determined as per the clinical status at the last recorded Histopathologic inflammation 10 (67) clinical visit. An outcome was defined as favorable if there was Laboratory parameters ESR, mm/hr 15 (3–>130) a recorded improvement in pain symptoms and functional per- CRP, mg/dL 0.4 (<0.1–10.3) formance relative to a patient’s preintervention clinical status, WBC count (synovial fluid), cells/mm 2648 (4–141 546) without requirement for unplanned additional surgical debride- %Neutrophils (synovial fluid) 86 (0–98) ment for putative persistent infection. Statistical analysis was per- Radiologic findings formed using Fisher’s exact test and the Wilcoxon rank-sum test. Radiolucency 4 (20) Component Loosening 2 (10) A P value of <.05 was considered to be statistically significant. Subluxation 2 (10) Fracture 1 (5) RESULTS Osteolysis 0 (0) There were 24 cases of P. acnes prosthetic shoulder joint infections Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PJI, prosthetic identified over the 14-year period of this study. Of these, 11 (46%) joint infection; WBC, white blood cell. Data are number (%) of cases, unless otherwise indicated. met criteria for definite infection and 13 (54%) met criteria for Median (range of values for PJI cases). probable infection. Right and left shoulder sites were similarly af- fected (54% and 46%, respectively). The demographic and clinical characteristics of these cases are reflected in Tables 1 and 4. percentage of 86% (n = 13). Of 15 cases undergoing operative in- tervention, intraoperative purulence was noted in 47% and tissue Clinical and Laboratory Characteristics The median time from index surgery to diagnosis was 15.9 histopathologic inflammation in 67%. months (range, 0.4–251). The majority of diagnoses were delayed Radiologic Characteristics (42%) or late (46%), with only 3 cases (12%) diagnosed <3 Abnormal radiologic findings were noted in a minority of cases. months after surgery. All 24 cases presented with joint pain Radiolucency was observed in 20% of cases. Loosening of the (Table 1). The majority of cases (88%) demonstrated impaired prosthesis or subluxation was observed in 10% of cases, and range of motion. Joint swelling (21%), joint warmth (8%), joint fracture was observed in 5% of cases. No osteolysis was erythema (12%), and constitutional symptoms (8%) were un- observed. common. No fever or wound drainage was noted. There was no significant difference in clinical presentation by time to diag- Microbiologic Characteristics and Antimicrobial Susceptibility nosis (early vs delayed vs late) or by PJI type (definite vs probable Patterns infection). The proportion with an elevated ESR (>20 mm/hour) The majority of cases (92%) were identified after implementa- was 47% and elevated CRP (>0.5 mg/dL) was 44%. Peripheral tion of the extended culture protocol in 2009. The median time WBC data, when obtained, was primarily in the normal range. to culture positivity was 4.5 days (range, 3–14 days), which was The median synovial leukocyte count of aspirated joints was unchanged in the extended culture period. However, 7 (29%) 2648 cells/mm (n = 13), with median synovial neutrophil cases identified in the 2009–2013 period required a culture P. acnes Shoulder PJIs � OFID � 3 Table 3. Treatment Outcomes for Propionibacterium acnes Shoulder duration of >5 days for organism recovery. There was no signif- Prosthetic Joint Infection icant difference in clinical presentation for cases with recovery at >5 days relative to those with earlier culture detection. All Total Treated Favorable Outcome tested isolates were susceptible to β-lactams (penicillin, pipera- Treatment No. (%) No. (%) cillin/tazobactam, ertapenem), vancomycin, moxifloxacin, and Type of treatment* rifampin (Table 2). As is typical of P. acnes, all were resistant Antibiotic therapy only 7 (29) 4 (67) Antibiotic therapy + surgery 14 (58) 10 (71) to metronidazole. The rate of resistance to clindamycin was Surgical type* 6%. The MIC range for minocycline was 0.03–0.25 µg/mL. 1-stage exchange 4 (27) 3 (75) 2-stage exchange 7 (47) 6 (86) Rifampin therapy* Antimicrobial and Surgical Treatment Yes 15 (71) 11 (73) There were 21 patients (88%) who received antibiotic treatment No 5 (24) 3 (60) and 15 (62%) who received surgical intervention. There were 7 Data are number (% of treated cases). patients (29%) who received antibiotic treatment only and 14 Data are number (% of all cases). Data are number (% of surgical cases). (58%) who received concomitant antibiotic and surgical treat- Data are number (% of cases receiving antibiotic therapy). ment (Tables 3 and 4); 1 patient received surgical intervention * P > .05. without antibiotic therapy. Of the 15 surgical cases, 1 (7%) under- went debridement and retention, 4 (27%; 1 planned, 3 un- planned) underwent a 1-stage procedure, 7 (47%) underwent a Treatment Outcomes 2-stage procedure, and 3 (20%) underwent prosthesis removal The median follow-up duration was 24 months (range, 4.6– with spacer placement without reimplantation. All 3 prosthesis 65.9). Antibiotic-only approaches were first initiated in mid- removals were per patient preference. The median duration of an- 2009. Consequently, the median follow-up duration for those tibiotic administration was 6.3 months (range, 1.3–50.7); 7 receiving antibiotic therapy only was 12.2 months (range, 4.6– months (range, 4.1–50.7) for those receiving antibiotic only and 51) compared with 27.8 months (range, 7.3–65.9) for those re- 5.5 months (range, 1.3–21.3) for those receiving both antibiotic ceiving both antibiotic therapy and surgery (P = .14). and surgery. The majority of antibiotic regimens (67%) used a The proportion of cases with a favorable outcome was similar β-lactam (penicillin or amoxicillin). Other antimicrobial agents for those treated with antibiotic therapy and surgery (71%) used included minocycline or doxycycline, vancomycin, and clin- compared with those treated with antibiotic therapy only damycin. Rifampin was used in 15 (71%) cases. The median du- (67%) (Table 3; P = 1.0). Outcomes were similar for those who ration on rifampin therapy was 3.9 months (range, 0.3–17.8). Of underwent a 1-stage (75%) or 2-stage procedure (86%) (P = 1.0). the 7 cases receiving antibiotic therapy only, the rationale for the A favorable outcome was noted for 73% of cases with rifampin decision for no surgical intervention included the presence of therapy compared with 60% without rifampin therapy (P = .61). metastatic rectal cancer (1), poor surgical risk secondary to mul- However, of the 15 cases in which rifampin was administered, tiple comorbidities (1), insurance limitations (1), stable prosthesis this agent had to be discontinued in 6 (40%) due to adverse re- (1), limited pain (1), and patient preference (2). actions ranging from gastrointestinal and influenza-like symp- toms (resolved post cessation) to angioedema and severe rash Table 2. Microbial Susceptibility Patterns of Propionibacterium acnes including a case of acute generalized exanthematous pustulosis Isolates requiring hospitalization. Antimicrobial Agent No. (%) DISCUSSION Penicillin 19 (100) It has generally been considered that the optimal management Piperacillin/tazobactam 7 (100) of PJIs beyond the early period requires the combination of an- Ertapenem 7 (100) timicrobial therapy with surgical intervention [1, 3, 6, 14, 23]. Moxifloxacin 10 (100) Rifampin 6 (100) Antimicrobial therapy in the absence of surgical intervention Vancomycin 14 (100) has been considered to primarily result in unacceptably high Clindamycin 17 (94) rates of failed outcomes [1, 28]. However, few studies have ex- Metronidazole 0 (0) amined the comparative management of P. acnes infections Minocycline MIC 0.03–0.25 µg/mL with nonsurgical approaches. In this 14-year series of 24 Abbreviations: CLSI, Clinical and Laboratory Standards Institute; EUCAST, European P. acnes prosthetic shoulder infections, we found treatment Committee on Antimicrobial Susceptibility Testing; MIC, minimum inhibitory concentration. Data are number (%) of cases, unless otherwise indicated; susceptibilities determined as with a nonsurgical antibiotic-only approach to have an outcome per CLSI/EUCAST breakpoints. comparable to that of a traditional combined medical-surgical Range of MIC values for 11 tested isolates; no CLSI interpretive breakpoints are available for minocycline; tetracycline susceptible MIC breakpoint is ≤4 µg/mL. approach. Our findings suggest that for P. acnes shoulder 4 � OFID � Piggott et al Table 4. Individual Clinical Characteristics and Outcomes of 24 Patients With Propionibacterium acnes Shoulder Prosthetic Joint Infection Time to Culture Time From Index Laboratory Markers, Treatment Favorable Case Clinical Signs and Positivity– Days (No. of Surgery–Months (Year Radiographic and Operative (Antibiotic Clinical No. Symptoms Positive Specimens ) of Diagnosis) Findings Duration– Days) Outcome 1 Joint pain, ↓ROM 3 (3) 1.9 (2001) ESR > 130, CRP 10.3 Abx Yes Purulence, Tissue Surgery inflammation 2 stage Rifampin (45) 2 Joint pain, ↓ROM, Joint 3 (1) 7.1 (2009) ESR 7, CRP 0.3 Abx No swelling Surgery Debridement Rifampin (408) 3 Joint pain, ↓ROM, Joint 3 (1) 8.4 (2010) Tissue inflammation Abx Yes swelling, Erythema Surgery 1 stage Rifampin (580) 4 Joint pain, ↓ROM 4 (1) 6.5 (2012) ESR 5, CRP 0.1 Abx No Rifampin (196) 5 Joint pain, ↓ROM 4 (1) 15 (2009) Purulence, Tissue Abx Yes inflammation Surgery Removal Rifampin (118) 6 Joint pain, ↓ROM, Joint 4 (1) 16.7 (2011) ESR 30, CRP 2.1 Abx Yes swelling, Erythema Radiolucency Surgery Purulence, Tissue 2 stage inflammation Rifampin (162) 7 Joint pain, ↓ROM 4 (1) 4.6 (2011) Radiolucency, Component Abx Yes loosening Surgery Purulence, Tissue 2 Stage inflammation (83) 8 Joint pain, ↓ROM 4 (1) 7.4 (2009) ESR 10, CRP 0.4 Abx Yes Rifampin (1540) 9 Joint pain, ↓ROM 4 (1) 54.4 (2012) ESR 11, CRP 1.2 Abx LTFU Radiolucency 10 Joint pain, ↓ROM 4 (1) 9 (2009) Abx Yes Surgery 1 Stage Rifampin (349) 11 Joint pain, ↓ROM 4 (1) 251 (2010) Abx Yes Surgery 1 Stage Rifampin (419) 12 Joint pain, ↓ROM 4 (1) 37 (2012) ESR 8, CRP 0.1 Surgery No 1 Stage 13 Joint pain 5 (1) 4.3 (2009) ESR 40, CRP 2.3 Component Abx No loosening Tissue Surgery inflammation 2 Stage Rifampin (649) 14 Joint pain, ↓ROM, Joint 5 (1) 55.4 (2010) ESR 26, CRP 0.2 Abx Yes swelling Rifampin (232) 15 Joint pain, ↓ROM 5 (2) 12.4 (2008) ESR 20, CRP 0.3 Purulence Abx Yes Surgery 2 Stage Rifampin (420) 16 Joint pain, ↓ROM 5 (1) 112 (2012) ESR 25, CRP 0.3 Abx Yes Tissue inflammation Surgery 2 Stage (170) 17 Joint pain, ↓ROM, Warmth, 5 (1) 2.8 (2011) ESR 37, CRP 4 Abx Yes Constitutional symptoms Rifampin (770) P. acnes Shoulder PJIs � OFID � 5 Table 4 continued. Time to Culture Time From Index Laboratory Markers, Treatment Favorable Case Clinical Signs and Positivity– Days (No. of Surgery–Months (Year Radiographic and Operative (Antibiotic Clinical No. Symptoms Positive Specimens ) of Diagnosis) Findings Duration– Days) Outcome 18 Joint pain, ↓ROM 7 (1) 232.8 (2013) Radiolucency, Subluxation Abx No Purulence, Tissue Surgery inflammation Removal (89) 19 Joint pain, ↓ROM 8 (1) 114.8 (2012) ESR 5, CRP < 0.1 Abx Yes Rifampin (126) 20 Joint pain, ↓ROM, Joint 8 (1) 89.3 (2009) ESR 80, CRP 4.1 Abx No swelling, Erythema, Fracture Purulence, Surgery Warmth, Constitutional Tissue inflammation Removal symptoms Rifampin (46) 21 Joint pain 8 (1) 27.4 (2013) Abx No (189) 22 Joint pain, ↓ROM 9 (1) 0.4 (2011) ESR 3, CRP 0.1 Abx Yes Tissue inflammation Surgery 2 Stage (41) 23 Joint pain, ↓ROM 9 (2) 163.7 (2011) Subluxation LTFU LTFU 24 Joint pain, ↓ROM 14 (1) 41.9 (2011) CRP 0.8 LTFU LTFU Abbreviations: Abx, antibiotic therapy; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LTFU, lost to follow up; ROM, range of motion. Number of positive specimens = total number of specimens attained. PJIs, an initial nonsurgical antibiotic-only approach may find institution of an extended P. acnes culture protocol. Twenty- relevance for select patients with stable prostheses, particularly nine percent of P. acnes PJIs would have been missed otherwise, for those in whom surgical intervention may be contraindicated affirming the importance of these techniques [29]. or declined. In clinical settings, the majority of cases in our series occurred Prior series have suggested the incorporation of rifampin into among males. These cases were primarily delayed or late presen- the antimicrobial management of P. acnes shoulder infections tations as observed in prior reports [17, 19, 22].Themalepredom- [18, 19]. Rifampin has been considered active against biofilms, inance for P. acnes shoulder PJIs correlates with the previously the formation of which has been considered integral to the path- reported higher P. acnes bacterial burden for men compared ogenesis of P. acnes in prosthetic and other device-related infec- with women at shoulder sites [10].Theindolentnatureofthisor- tions [11, 31]. Propionibacterium acnes isolates associated with ganism likely accounts for its predominantly late presentation. The invasive prosthetic infections have been shown to have stronger majority of PJIs in this series presented with pain and functional biofilm formation capability than isolates from healthy skin [32]. limitation without fever or constitutional symptoms. Whereas the Such biofilm-associated isolates have demonstrated increased an- presence of joint pain in all cases may seem evident, such universal timicrobial resistance in vitro [33, 34]. Moreover, there has been occurrence has not been reported in other series [17]. Previous re- in vivo animal data suggesting the efficacy of rifampin against P. ports have also suggested the occurrence of more apparent clinical acnes foreign-body-associated infections [35]. Recent Infectious symptoms with early PJIs [1]. However, we noted no difference in Diseases Society of America guidelines recommend penicillin clinical presentation by time to presentation. or ceftriaxone as first-line treatment for P. acnes PJIs with clinda- Propionibacterium acnes infections have often been charac- mycin or vancomycin as alternatives, and minocycline or doxy- terized by the absence of elevated inflammatory markers [1]. cycline for suppressive therapy [3]. Adjunctive rifampin therapy However, inflammatory marker elevation has been noted in a is not included in these recommendations for P. acnes PJI man- significant proportion of cases in some series, occurring in agement. In this series, treatment outcomes were comparable over 70% of cases in 1 recent study [22, 36]. In our series, a no- with and without rifampin therapy. However, this drug was poor- table proportion of PJIs occurred without elevated inflammato- ly tolerated and prematurely discontinued in 40% of cases. These ry markers, yet there was still evidence of inflammatory marker findings suggest therolefor rifampin in themanagementof elevation in just under 50% of cases. Intraoperative purulence P. acnes PJIs requires further study. was similarly noted in just <50% of cases. The proportion of Recent studies have demonstrated the need for extended cul- cases with histopathologic inflammation in our series (67%) tures to maximize recovery of pathogenic P. acnes isolates [27, was similar to previously reported observations [29, 37]. 29].In concordance with these findings, we observed a significant There have been reports of a shift in antimicrobial suscepti- increase in the number of P. acnes shoulder PJIs subsequent to bility patterns of P. acnes in the setting of the increasing use of 6 � OFID � Piggott et al antimicrobial agents for acne vulgaris [25, 26, 38]. Yet, varied from patient preference and limited symptoms (ie, solid there have been reports of phylogenetic differences between prosthesis with mild clinical symptoms) to severe comorbid dis- acne-related P. acnes isolates and deep device-related P. acnes ease (ie, nonoperative candidate), suggesting a wide clinical isolates, suggesting shifting acne-related resistance patterns spectrum of host conditions selected for this approach, reducing may not reflect trends in susceptibility patterns for deep-seated, the likelihood of this effect. All cases were treated with suscep- prosthetic-related infections [11]. However, there have also been tible drugs. reports of increased antimicrobial resistance for biofilm-associ- CONCLUSIONS ated P. acnes isolates in vitro [33–35]. Furthermore, there have been recent reports of penicillin resistance even for P. acnes iso- Overall, this study contributes to better defining clinical charac- lates recovered from the shoulder joint [39]. In this series, all teristics of P. acnes prosthetic shoulder infections. Furthermore, isolates tested were susceptible to vancomycin, rifampin, and it is one of the few descriptions of the potential utility of non- β-lactams including penicillin. There was limited resistance surgical management approaches for P. acnes infections, which noted to clindamycin. Despite widespread use of the tetracy- could include a trial of antibiotic therapy prior to surgical con- cline class for acne, minocycline MICs for this study population siderations. Future, larger studies prospectively evaluating alter- were all within the expected susceptibility range. The observed native surgical and nonsurgical management approaches, oral susceptibility patterns were similar to those of other recent se- versus parenteral therapy, optimal antibiotic duration, and ap- ries of P. acnes shoulder isolates and suggest that in general, the propriate patient selection will be needed for the further optimi- broad antimicrobial susceptibility of P. acnes isolates in deep zation of the clinical management of P acnes infections. shoulder PJIs appears to be maintained [29, 39]. Acknowledgments This study does carry the limitations of a primarily descrip- We acknowledge Deborah Popoli and Qumars Roshanian (Johns Hop- tive retrospective case series, without predefined diagnostic and kins University School of Medicine, Department of Pathology) for assistance therapeutic procedures, which could bias result interpretation. with data management. Financial support. This work was supported by the Johns Hopkins Assessment of clinical outcomes was also primarily qualitative. University School of Medicine, Sherrilyn and Ken Fisher Center for Envi- However, it is accepted that the primary goal of prosthetic joint ronmental Infectious Diseases. replacement and PJI treatment is to improve quality of life by Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Con- striving for a painless and functional joint, which were the cri- flicts of Interest. teria used to define a favorable study outcome [1, 6]. No gold standard exists for PJI diagnosis. However, we adapted previ- References ously applied criteria in our case definition [1, 3, 22, 29, 30]. 1. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med 2009; 361:787–94. On retrospective review, limited specimens were obtained for 2. Kurtz S, Ong K, Lau E, et al. 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The shorter median follow-up time for the antibiotic- human shoulder. J Shoulder Elbow Surg 2009; 18:897–902. 11. Achermann Y, Goldstein EJ, Coenye T, Shirtliff ME. Propionibacterium acnes: only group provided less time for observation of clinical out- from commensal to opportunistic biofilm-associated implant pathogen. Clin Mi- comes. In addition, antibiotic-only cases were all diagnosed crobiol Rev 2014; 27:419–40. 12. Conen A, Walti LN, Merlo A, et al. Characteristics and treatment outcome of ce- via joint arthrocentesis without operative intervention and rebrospinal fluid shunt-associated infections in adults: a retrospective analysis over were thus all classified as probable infections. However, we an 11-year period. Clin Infect Dis 2008; 47:73–82. 13. Perry A, Lambert P. Propionibacterium acnes: infection beyond the skin. Expert found no significant difference in the characteristics of these Rev Anti Infect Ther 2011; 9:1149–56. cases compared with those with more definitive operative and 14. Achermann Y, Sahin F, Schwyzer HK, et al. Characteristics and outcome of 16 periprosthetic shoulder joint infections. Infection 2013; 41:613–20. tissue findings for infection. Determination of which cases re- 15. Dodson CC, Craig EV, Cordasco FA, et al. Propionibacterium acnes infection after ceived an antibiotic-only approach could have been subject to shoulder arthroplasty: a diagnostic challenge. J Shoulder Elbow Surg 2010; selection bias. However, the rationale behind such case selection 19:303–7. P. acnes Shoulder PJIs � OFID � 7 16. Grosso MJ, Sabesan VJ, Ho JC, et al. Reinfection rates after 1-stage revision shoul- 31. Bayston R, Ashraf W, Barker-Davies R, et al. Biofilm formation by Propionibacte- der arthroplasty for patients with unexpected positive intraoperative cultures. 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Antimicrobial susceptibility and genetic character- problem. Dermatology 2003; 206:54–6. istics of Propionibacterium acnes isolated from patients with acne. Int J Dermatol 26. Mendoza N, Hernandez PO, Tyring SK, et al. Antimicrobial susceptibility of Pro- 2013; 52:418–25. pionibacterium acnes isolates from acne patients in Colombia. Int J Dermatol 39. Crane JK, Hohman DW, Nodzo SR, Duquin TR. Antimicrobial susceptibility of 2013; 52:688–92. Propionibacterium acnes isolates from shoulder surgery. Antimicrob Agents Che- 27. Schafer P, Fink B, Sandow D, et al. Prolonged bacterial culture to identify late peri- mother 2013; 57:3424–6. prosthetic joint infection: a promising strategy. Clin Infect Dis 2008; 47:1403–9. 40. Hudek R, Sommer F, Kerwat M, et al. Propionibacterium acnes in shoulder sur- 28. Coste JS, Reig S, Trojani C, et al. The management of infection in arthroplasty of gery: true infection, contamination, or commensal of the deep tissue? J Shoulder the shoulder. 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J Clin Microbiol 2013; 51:731–2. 8 � OFID � Piggott et al http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults

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Abstract

Open Forum Infectious Diseases MAJOR A RTICLE Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults 1,4 1 1 5 1,2 3 1,6 Damani A. Piggott, Yvonne M. Higgins, Michael T. Melia, Brandon Ellis, Karen C. Carroll, Edward G. McFarland, and Paul G. Auwaerter 1 2 3 Division of Infectious Diseases, Division of Medical Microbiology, Department of Pathology, Division of Shoulder Surgery, Department of Orthopedic Surgery, Johns Hopkins University School 4 5 6 of Medicine, and Department of Epidemiology, Johns Hopkins University School of Public Health, Johns Hopkins Hospital Microbiology Laboratory, and Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, Baltimore, Maryland Background. Prosthetic joint infections (PJIs) significantly complicate joint arthroplasties. Propionibacterium acnes is an in- creasingly recognized PJI pathogen, yet limited clinical and therapeutic data exist. We sought to examine characteristics of P. acnes shoulder PJIs and compare surgical and nonsurgical management outcomes. Methods. A retrospective analysis of P. acnes shoulder PJIs was conducted at an academic center in Baltimore, Maryland from 2000 to 2013. Results. Of 24 cases of P. acnes shoulder PJIs, 92% were diagnosed after extended culture implementation; 42% in the delayed and 46% in the late postsurgical period. Joint pain and diminished function were the predominant presenting clinical signs. Eryth- rocyte sedimentation rate and C-reactive protein elevations occurred in 47% and 44%, respectively. All tested isolates were susceptible to β-lactams, moxifloxacin, vancomycin, and rifampin. Clindamycin resistance was identified in 6%. Of the antibiotic-only treated cases, 67% had a favorable clinical outcome compared with 71% (P = 1.0) of cases with a combined antibiotic-surgical approach. Favorable outcome with and without rifampin therapy was 73% and 60% (P = .61), respectively. Conclusions. Propionibacterium acnes PJI diagnoses increased with extended culture. Inflammatory markers were elevated in a minority of cases. Isolates maintained broad antimicrobial susceptibility. Compared to combined antibiotic-surgical approaches, an- tibiotic-only approaches were similarly successful in selected cases. Keywords. antimicrobial susceptibility; Propionibacterium acnes; prosthetic joint infection; shoulder prosthesis. Over 1 million prosthetic joints are placed in the United States region [8–10]. Initially considered an important agent in the each year. With an aging population, this number is projected pathogenesis of acne vulgaris, P. acnes has been more recently to increase 4-fold over the next 2 decades [1–3]. A notable propor- implicated in serious deep-seated postoperative and medical tion of these joints subsequently fail. Prosthetic joint infections device-related infections, particularly PJIs [11–13]. With (PJIs) have been considered to be the most serious cause of sub- improved diagnostics, including extended culture protocols, P. sequent joint failure, occurring in up to an estimated 2% of arthro- acnes has been specifically recognized as a dominant organism plasties [1, 4–6]. In addition to the clinical impact, the economic in infections involving shoulder prostheses [14–23]. Yet, there burden of PJIs is markedly high, with an estimated cost in the has been a paucity of data on the clinical and microbiologic United States approaching 1 billion dollars annually [5, 7]. characteristics of such infections. Propionibacterium acnes is a Gram-positive anaerobic bacil- Treatment of PJIs beyond the acute postoperative period has lus. It is a human commensal organism, primarily found in skin traditionally relied on an appropriate antimicrobial regimen, and superficial mucosal sites, with a predilection for piloseba- combined with a surgical approach dependent on stability of ceous follicles that exist in the upper body such as the shoulder the prosthesis, state of the periprosthetic tissue, patient comor- bidity, and characteristics of the infecting organism [1,3,6].Sur- gical options include debridement with implant retention or antibiotic spacer implantation with no subsequent arthroplasty, Received 23 September 2015; accepted 30 December 2015. Correspondence: D. A. Piggott, Division of Infectious Diseases, Johns Hopkins University a 1-stage revision with immediate reimplantation of a new pros- School of Medicine, 2213 McElderry Street, Room M141, Baltimore, MD 21205 (dpiggot1@ thesis, a 2-stage revision with reimplantation several months jhmi.edu). after prosthesis removal, permanent prosthesis removal, and Open Forum Infectious Diseases © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society amputation. Medical management options have been manifold, of America. This is an Open Access article distributed under the terms of the Creative Commons largely because antimicrobial activity against P. acnes has been Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, reported for a wide spectrum of agents [24]. However, with the provided the original work is not altered or transformed in any way, and that the work is properly increasing use of antimicrobial agents for acne vulgaris, advanc- cited. For commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ ing resistance of P. acnes isolates has been reported, particularly ofv191 P. acnes Shoulder PJIs � OFID � 1 in refractory cases of acne [25–27]. The susceptibility patterns of spot tests, and/or biochemical reagents. The extended culture P. acnes isolates implicated in deep-seated infections have been incubation protocol for P. acnes was implemented in January less well characterized. 2009, with extension from 5 to 14 days of incubation for both Medical management of PJIs without surgical intervention aerobic and anaerobic culture media. has been considered to result in poorer clinical outcomes [1, Definition 28]. Such a limited approach has typically been reserved for pa- A PJI was defined based on previously detailed criteria [1, 3, 22, tients with inoperable status [1, 6]. Occasionally, this strategy 29, 30]. A case was considered definite (1) if 2 or more culture has been considered in clinical practice for low virulence organ- specimens were positive for P. acnes with no other organisms on isms, although with limited supporting data. Propionibacterium culture or (2) if 1 culture specimen was positive for P. acnes with acnes has been considered a low virulence organism, but little no other organisms on culture and there was evidence of either data exists on the comparative advantage of combined medical joint purulence, histopathologic inflammation, or a sinus tract and surgical management to that of medical management alone communicating with the prosthesis. A case was considered for infections involving this organism. probable if 1 culture specimen was found to be positive for P. We performed a retrospective analysis to describe clinical and acnes and 1 of the following concomitant symptoms was pre- laboratory characteristics of P. acnes prosthetic shoulder joint sent:fever,constitutionalsymptoms(chills,fatigue, night infections and antimicrobial susceptibility patterns of the asso- sweats, weight loss, and anorexia), joint pain, joint swelling, ciated isolates over a 14-year period. We further describe short- joint warmth, wound drainage, or loss of range of motion. term treatment outcomes for surgical and alternative medical Cases were excluded if there was an alternative explanation approaches to the management of these infections. for these symptoms (such as gout or rheumatoid arthritis re- sponsive to therapy). There were no coexisting pathogens isolat- PATIENTS AND METHODS ed in any of the cases included in this study. Hospital Setting and Study Population Data Collection This study was conducted at the Johns Hopkins Hospital and Medical chart abstraction was performed using a standardized Clinics in Baltimore, Maryland. Linkage to the Johns Hopkins case report form to retrieve demographic, clinical, and laboratory Hospital microbiology database system was used to identify data. Demographic data included age, sex, and race. Laboratory cases from January 2000 through December 2013. Patients data included erythrocyte sedimentation rate (ESR), C-reactive aged 18 years and older with a positive P. acnes culture from protein (CRP), white blood cell (WBC) count, and percentage the shoulder joint with a prior shoulder prosthesis were identi- of neutrophils in the blood and synovial fluid. Imaging findings fied for study inclusion. This study was approved by the Johns from plain films and computerized tomography scans were re- Hopkins Institutional Review Board. corded. Laboratory and radiologic data recorded at diagnosis re- flect findings before any surgical PJI treatment. The time from Specimen Collection and Microbiologic Assessment index surgery to diagnosis was recorded as the time from the Joint fluid aspirates and operative tissue specimens were collect- last surgical procedure performed prediagnosis to the first pos- ed using standard protocols and transported to the Microbiol- itive P. acnes culture. Episodes were classified as early (<3 ogy Laboratory for processing. Joint fluid aspirates were months after surgery), delayed (3–24 months), or late (>24 transported in BD BBL Port-A-Cul vials (Becton, Dickinson months) as previously described [6]. Time to culture positivity and Company, Sparks, MD), and tissue specimens were placed was recorded as the time from joint specimen attainment to in a sterile container and transported to the Microbiology Lab- positive culture growth. oratory within 1 hour of collection. Specimens were then pro- cessed and inoculated onto standard agars, including Brucella Antimicrobial Susceptibility Patterns blood agar (Anaerobe Systems, Morgan Hill, CA), and BD The susceptibilities of P. acnes isolates were tested against a BBL Chopped Meat Broth (Becton, Dickinson and Company). range of standard antimicrobial agents. Isolates were classified Aerobic plates and chopped meat broths were incubated in 5% as susceptible as per the minimum inhibitory concentration CO at 35°C. Anaerobic plates and broth subcultures were incu- (MIC) breakpoints set by the Clinical and Laboratory Standards bated in an AS-580 anaerobe chamber (Anaerobe Systems) at Institute (CLSI): penicillin (≤0.5 µg/mL), piperacillin/tazobac- 35°C. Aerobic blood and chocolate agar plates, as well as anaer- tam (≤32/4 µg/mL), ertapenem (≤4 µg/mL), clindamycin obic Brucella and Phenyl-Ethyl-Alcohol agar plates, were held (≤2µg/mL), moxifloxacin (≤2µg/mL), and metronidazole for 14 days. Chopped meat broths were subcultured both aero- (≤8 µg/mL) or by the European Committee on Antimicrobial bically and anaerobically when turbid or terminally subcultured Susceptibility Testing (EUCAST): vancomycin (<2 µg/mL) at day 10 if clear. Organism identification was obtained using and rifampin (≤0.5 µg/mL) [11]. No CLSI or EUCAST break- the Bruker Microflex LT MALDI-TOF mass spectrometry sys- points were available for minocycline. The absolute MICs for tem (Bruker Daltonics, Billerica, MA), as well as Gram stain, isolates against minocycline are thus reported. Susceptibility 2 � OFID � Piggott et al Table 1. Demographic and Clinical Characteristics of 24 Patients With testing for penicillin was initiated in 2001; susceptibility testing Propionibacterium acnes Shoulder Prosthetic Joint Infection for clindamycin, moxifloxacin, and vancomycin was initiated in 2009; susceptibility testing for piperacillin/tazobactam, ertape- Variable No. (%) nem, and metronidazole was initiated in 2010; and susceptibil- Age, years 62 (40, 81) ity testing for rifampin was initiated in 2012. Male 19 (79) White 21 (88) Follow-Up and Treatment Outcomes Time from index surgery Antimicrobial therapeutic regimens and treatment outcomes Early (<3 mo) 3 (12) were assessed through the last recorded clinical visit. Decisions Delayed (3–24 mo) 10 (42) on therapeutic regimens were based on the clinical judgment of Late (>24 mo) 11 (46) the infectious disease and surgical specialist providers. The type, Time from specimen collection to culture positivity, days 4.5 (3–14) Clinical signs and symptoms delivery method, and duration of antimicrobial therapy were re- Joint pain 24 (100) corded. In all cases, susceptibility profiles informed drug choice. Loss of range of motion 21 (88) Concomitant use of rifampin was also per the clinical judgment Swelling 5 (21) of the infectious disease physician with consideration of patient Erythema 3 (12) tolerability. Chart abstraction did not allow for precise determi- Warmth 2 (8) Constitutional symptoms 2 (8) nation of duration of intravenous (IV) versus oral therapy. How- Wound drainage 0 (0) ever, of those who received IV antimicrobial therapy, the majority Fever 0 (0) of patients received at least a 4- to 6-week course of IV therapy Intraoperative findings prior to transition to an oral regimen. The final clinical outcome Purulence 7 (47) was determined as per the clinical status at the last recorded Histopathologic inflammation 10 (67) clinical visit. An outcome was defined as favorable if there was Laboratory parameters ESR, mm/hr 15 (3–>130) a recorded improvement in pain symptoms and functional per- CRP, mg/dL 0.4 (<0.1–10.3) formance relative to a patient’s preintervention clinical status, WBC count (synovial fluid), cells/mm 2648 (4–141 546) without requirement for unplanned additional surgical debride- %Neutrophils (synovial fluid) 86 (0–98) ment for putative persistent infection. Statistical analysis was per- Radiologic findings formed using Fisher’s exact test and the Wilcoxon rank-sum test. Radiolucency 4 (20) Component Loosening 2 (10) A P value of <.05 was considered to be statistically significant. Subluxation 2 (10) Fracture 1 (5) RESULTS Osteolysis 0 (0) There were 24 cases of P. acnes prosthetic shoulder joint infections Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PJI, prosthetic identified over the 14-year period of this study. Of these, 11 (46%) joint infection; WBC, white blood cell. Data are number (%) of cases, unless otherwise indicated. met criteria for definite infection and 13 (54%) met criteria for Median (range of values for PJI cases). probable infection. Right and left shoulder sites were similarly af- fected (54% and 46%, respectively). The demographic and clinical characteristics of these cases are reflected in Tables 1 and 4. percentage of 86% (n = 13). Of 15 cases undergoing operative in- tervention, intraoperative purulence was noted in 47% and tissue Clinical and Laboratory Characteristics The median time from index surgery to diagnosis was 15.9 histopathologic inflammation in 67%. months (range, 0.4–251). The majority of diagnoses were delayed Radiologic Characteristics (42%) or late (46%), with only 3 cases (12%) diagnosed <3 Abnormal radiologic findings were noted in a minority of cases. months after surgery. All 24 cases presented with joint pain Radiolucency was observed in 20% of cases. Loosening of the (Table 1). The majority of cases (88%) demonstrated impaired prosthesis or subluxation was observed in 10% of cases, and range of motion. Joint swelling (21%), joint warmth (8%), joint fracture was observed in 5% of cases. No osteolysis was erythema (12%), and constitutional symptoms (8%) were un- observed. common. No fever or wound drainage was noted. There was no significant difference in clinical presentation by time to diag- Microbiologic Characteristics and Antimicrobial Susceptibility nosis (early vs delayed vs late) or by PJI type (definite vs probable Patterns infection). The proportion with an elevated ESR (>20 mm/hour) The majority of cases (92%) were identified after implementa- was 47% and elevated CRP (>0.5 mg/dL) was 44%. Peripheral tion of the extended culture protocol in 2009. The median time WBC data, when obtained, was primarily in the normal range. to culture positivity was 4.5 days (range, 3–14 days), which was The median synovial leukocyte count of aspirated joints was unchanged in the extended culture period. However, 7 (29%) 2648 cells/mm (n = 13), with median synovial neutrophil cases identified in the 2009–2013 period required a culture P. acnes Shoulder PJIs � OFID � 3 Table 3. Treatment Outcomes for Propionibacterium acnes Shoulder duration of >5 days for organism recovery. There was no signif- Prosthetic Joint Infection icant difference in clinical presentation for cases with recovery at >5 days relative to those with earlier culture detection. All Total Treated Favorable Outcome tested isolates were susceptible to β-lactams (penicillin, pipera- Treatment No. (%) No. (%) cillin/tazobactam, ertapenem), vancomycin, moxifloxacin, and Type of treatment* rifampin (Table 2). As is typical of P. acnes, all were resistant Antibiotic therapy only 7 (29) 4 (67) Antibiotic therapy + surgery 14 (58) 10 (71) to metronidazole. The rate of resistance to clindamycin was Surgical type* 6%. The MIC range for minocycline was 0.03–0.25 µg/mL. 1-stage exchange 4 (27) 3 (75) 2-stage exchange 7 (47) 6 (86) Rifampin therapy* Antimicrobial and Surgical Treatment Yes 15 (71) 11 (73) There were 21 patients (88%) who received antibiotic treatment No 5 (24) 3 (60) and 15 (62%) who received surgical intervention. There were 7 Data are number (% of treated cases). patients (29%) who received antibiotic treatment only and 14 Data are number (% of all cases). Data are number (% of surgical cases). (58%) who received concomitant antibiotic and surgical treat- Data are number (% of cases receiving antibiotic therapy). ment (Tables 3 and 4); 1 patient received surgical intervention * P > .05. without antibiotic therapy. Of the 15 surgical cases, 1 (7%) under- went debridement and retention, 4 (27%; 1 planned, 3 un- planned) underwent a 1-stage procedure, 7 (47%) underwent a Treatment Outcomes 2-stage procedure, and 3 (20%) underwent prosthesis removal The median follow-up duration was 24 months (range, 4.6– with spacer placement without reimplantation. All 3 prosthesis 65.9). Antibiotic-only approaches were first initiated in mid- removals were per patient preference. The median duration of an- 2009. Consequently, the median follow-up duration for those tibiotic administration was 6.3 months (range, 1.3–50.7); 7 receiving antibiotic therapy only was 12.2 months (range, 4.6– months (range, 4.1–50.7) for those receiving antibiotic only and 51) compared with 27.8 months (range, 7.3–65.9) for those re- 5.5 months (range, 1.3–21.3) for those receiving both antibiotic ceiving both antibiotic therapy and surgery (P = .14). and surgery. The majority of antibiotic regimens (67%) used a The proportion of cases with a favorable outcome was similar β-lactam (penicillin or amoxicillin). Other antimicrobial agents for those treated with antibiotic therapy and surgery (71%) used included minocycline or doxycycline, vancomycin, and clin- compared with those treated with antibiotic therapy only damycin. Rifampin was used in 15 (71%) cases. The median du- (67%) (Table 3; P = 1.0). Outcomes were similar for those who ration on rifampin therapy was 3.9 months (range, 0.3–17.8). Of underwent a 1-stage (75%) or 2-stage procedure (86%) (P = 1.0). the 7 cases receiving antibiotic therapy only, the rationale for the A favorable outcome was noted for 73% of cases with rifampin decision for no surgical intervention included the presence of therapy compared with 60% without rifampin therapy (P = .61). metastatic rectal cancer (1), poor surgical risk secondary to mul- However, of the 15 cases in which rifampin was administered, tiple comorbidities (1), insurance limitations (1), stable prosthesis this agent had to be discontinued in 6 (40%) due to adverse re- (1), limited pain (1), and patient preference (2). actions ranging from gastrointestinal and influenza-like symp- toms (resolved post cessation) to angioedema and severe rash Table 2. Microbial Susceptibility Patterns of Propionibacterium acnes including a case of acute generalized exanthematous pustulosis Isolates requiring hospitalization. Antimicrobial Agent No. (%) DISCUSSION Penicillin 19 (100) It has generally been considered that the optimal management Piperacillin/tazobactam 7 (100) of PJIs beyond the early period requires the combination of an- Ertapenem 7 (100) timicrobial therapy with surgical intervention [1, 3, 6, 14, 23]. Moxifloxacin 10 (100) Rifampin 6 (100) Antimicrobial therapy in the absence of surgical intervention Vancomycin 14 (100) has been considered to primarily result in unacceptably high Clindamycin 17 (94) rates of failed outcomes [1, 28]. However, few studies have ex- Metronidazole 0 (0) amined the comparative management of P. acnes infections Minocycline MIC 0.03–0.25 µg/mL with nonsurgical approaches. In this 14-year series of 24 Abbreviations: CLSI, Clinical and Laboratory Standards Institute; EUCAST, European P. acnes prosthetic shoulder infections, we found treatment Committee on Antimicrobial Susceptibility Testing; MIC, minimum inhibitory concentration. Data are number (%) of cases, unless otherwise indicated; susceptibilities determined as with a nonsurgical antibiotic-only approach to have an outcome per CLSI/EUCAST breakpoints. comparable to that of a traditional combined medical-surgical Range of MIC values for 11 tested isolates; no CLSI interpretive breakpoints are available for minocycline; tetracycline susceptible MIC breakpoint is ≤4 µg/mL. approach. Our findings suggest that for P. acnes shoulder 4 � OFID � Piggott et al Table 4. Individual Clinical Characteristics and Outcomes of 24 Patients With Propionibacterium acnes Shoulder Prosthetic Joint Infection Time to Culture Time From Index Laboratory Markers, Treatment Favorable Case Clinical Signs and Positivity– Days (No. of Surgery–Months (Year Radiographic and Operative (Antibiotic Clinical No. Symptoms Positive Specimens ) of Diagnosis) Findings Duration– Days) Outcome 1 Joint pain, ↓ROM 3 (3) 1.9 (2001) ESR > 130, CRP 10.3 Abx Yes Purulence, Tissue Surgery inflammation 2 stage Rifampin (45) 2 Joint pain, ↓ROM, Joint 3 (1) 7.1 (2009) ESR 7, CRP 0.3 Abx No swelling Surgery Debridement Rifampin (408) 3 Joint pain, ↓ROM, Joint 3 (1) 8.4 (2010) Tissue inflammation Abx Yes swelling, Erythema Surgery 1 stage Rifampin (580) 4 Joint pain, ↓ROM 4 (1) 6.5 (2012) ESR 5, CRP 0.1 Abx No Rifampin (196) 5 Joint pain, ↓ROM 4 (1) 15 (2009) Purulence, Tissue Abx Yes inflammation Surgery Removal Rifampin (118) 6 Joint pain, ↓ROM, Joint 4 (1) 16.7 (2011) ESR 30, CRP 2.1 Abx Yes swelling, Erythema Radiolucency Surgery Purulence, Tissue 2 stage inflammation Rifampin (162) 7 Joint pain, ↓ROM 4 (1) 4.6 (2011) Radiolucency, Component Abx Yes loosening Surgery Purulence, Tissue 2 Stage inflammation (83) 8 Joint pain, ↓ROM 4 (1) 7.4 (2009) ESR 10, CRP 0.4 Abx Yes Rifampin (1540) 9 Joint pain, ↓ROM 4 (1) 54.4 (2012) ESR 11, CRP 1.2 Abx LTFU Radiolucency 10 Joint pain, ↓ROM 4 (1) 9 (2009) Abx Yes Surgery 1 Stage Rifampin (349) 11 Joint pain, ↓ROM 4 (1) 251 (2010) Abx Yes Surgery 1 Stage Rifampin (419) 12 Joint pain, ↓ROM 4 (1) 37 (2012) ESR 8, CRP 0.1 Surgery No 1 Stage 13 Joint pain 5 (1) 4.3 (2009) ESR 40, CRP 2.3 Component Abx No loosening Tissue Surgery inflammation 2 Stage Rifampin (649) 14 Joint pain, ↓ROM, Joint 5 (1) 55.4 (2010) ESR 26, CRP 0.2 Abx Yes swelling Rifampin (232) 15 Joint pain, ↓ROM 5 (2) 12.4 (2008) ESR 20, CRP 0.3 Purulence Abx Yes Surgery 2 Stage Rifampin (420) 16 Joint pain, ↓ROM 5 (1) 112 (2012) ESR 25, CRP 0.3 Abx Yes Tissue inflammation Surgery 2 Stage (170) 17 Joint pain, ↓ROM, Warmth, 5 (1) 2.8 (2011) ESR 37, CRP 4 Abx Yes Constitutional symptoms Rifampin (770) P. acnes Shoulder PJIs � OFID � 5 Table 4 continued. Time to Culture Time From Index Laboratory Markers, Treatment Favorable Case Clinical Signs and Positivity– Days (No. of Surgery–Months (Year Radiographic and Operative (Antibiotic Clinical No. Symptoms Positive Specimens ) of Diagnosis) Findings Duration– Days) Outcome 18 Joint pain, ↓ROM 7 (1) 232.8 (2013) Radiolucency, Subluxation Abx No Purulence, Tissue Surgery inflammation Removal (89) 19 Joint pain, ↓ROM 8 (1) 114.8 (2012) ESR 5, CRP < 0.1 Abx Yes Rifampin (126) 20 Joint pain, ↓ROM, Joint 8 (1) 89.3 (2009) ESR 80, CRP 4.1 Abx No swelling, Erythema, Fracture Purulence, Surgery Warmth, Constitutional Tissue inflammation Removal symptoms Rifampin (46) 21 Joint pain 8 (1) 27.4 (2013) Abx No (189) 22 Joint pain, ↓ROM 9 (1) 0.4 (2011) ESR 3, CRP 0.1 Abx Yes Tissue inflammation Surgery 2 Stage (41) 23 Joint pain, ↓ROM 9 (2) 163.7 (2011) Subluxation LTFU LTFU 24 Joint pain, ↓ROM 14 (1) 41.9 (2011) CRP 0.8 LTFU LTFU Abbreviations: Abx, antibiotic therapy; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LTFU, lost to follow up; ROM, range of motion. Number of positive specimens = total number of specimens attained. PJIs, an initial nonsurgical antibiotic-only approach may find institution of an extended P. acnes culture protocol. Twenty- relevance for select patients with stable prostheses, particularly nine percent of P. acnes PJIs would have been missed otherwise, for those in whom surgical intervention may be contraindicated affirming the importance of these techniques [29]. or declined. In clinical settings, the majority of cases in our series occurred Prior series have suggested the incorporation of rifampin into among males. These cases were primarily delayed or late presen- the antimicrobial management of P. acnes shoulder infections tations as observed in prior reports [17, 19, 22].Themalepredom- [18, 19]. Rifampin has been considered active against biofilms, inance for P. acnes shoulder PJIs correlates with the previously the formation of which has been considered integral to the path- reported higher P. acnes bacterial burden for men compared ogenesis of P. acnes in prosthetic and other device-related infec- with women at shoulder sites [10].Theindolentnatureofthisor- tions [11, 31]. Propionibacterium acnes isolates associated with ganism likely accounts for its predominantly late presentation. The invasive prosthetic infections have been shown to have stronger majority of PJIs in this series presented with pain and functional biofilm formation capability than isolates from healthy skin [32]. limitation without fever or constitutional symptoms. Whereas the Such biofilm-associated isolates have demonstrated increased an- presence of joint pain in all cases may seem evident, such universal timicrobial resistance in vitro [33, 34]. Moreover, there has been occurrence has not been reported in other series [17]. Previous re- in vivo animal data suggesting the efficacy of rifampin against P. ports have also suggested the occurrence of more apparent clinical acnes foreign-body-associated infections [35]. Recent Infectious symptoms with early PJIs [1]. However, we noted no difference in Diseases Society of America guidelines recommend penicillin clinical presentation by time to presentation. or ceftriaxone as first-line treatment for P. acnes PJIs with clinda- Propionibacterium acnes infections have often been charac- mycin or vancomycin as alternatives, and minocycline or doxy- terized by the absence of elevated inflammatory markers [1]. cycline for suppressive therapy [3]. Adjunctive rifampin therapy However, inflammatory marker elevation has been noted in a is not included in these recommendations for P. acnes PJI man- significant proportion of cases in some series, occurring in agement. In this series, treatment outcomes were comparable over 70% of cases in 1 recent study [22, 36]. In our series, a no- with and without rifampin therapy. However, this drug was poor- table proportion of PJIs occurred without elevated inflammato- ly tolerated and prematurely discontinued in 40% of cases. These ry markers, yet there was still evidence of inflammatory marker findings suggest therolefor rifampin in themanagementof elevation in just under 50% of cases. Intraoperative purulence P. acnes PJIs requires further study. was similarly noted in just <50% of cases. The proportion of Recent studies have demonstrated the need for extended cul- cases with histopathologic inflammation in our series (67%) tures to maximize recovery of pathogenic P. acnes isolates [27, was similar to previously reported observations [29, 37]. 29].In concordance with these findings, we observed a significant There have been reports of a shift in antimicrobial suscepti- increase in the number of P. acnes shoulder PJIs subsequent to bility patterns of P. acnes in the setting of the increasing use of 6 � OFID � Piggott et al antimicrobial agents for acne vulgaris [25, 26, 38]. Yet, varied from patient preference and limited symptoms (ie, solid there have been reports of phylogenetic differences between prosthesis with mild clinical symptoms) to severe comorbid dis- acne-related P. acnes isolates and deep device-related P. acnes ease (ie, nonoperative candidate), suggesting a wide clinical isolates, suggesting shifting acne-related resistance patterns spectrum of host conditions selected for this approach, reducing may not reflect trends in susceptibility patterns for deep-seated, the likelihood of this effect. All cases were treated with suscep- prosthetic-related infections [11]. However, there have also been tible drugs. reports of increased antimicrobial resistance for biofilm-associ- CONCLUSIONS ated P. acnes isolates in vitro [33–35]. Furthermore, there have been recent reports of penicillin resistance even for P. acnes iso- Overall, this study contributes to better defining clinical charac- lates recovered from the shoulder joint [39]. In this series, all teristics of P. acnes prosthetic shoulder infections. Furthermore, isolates tested were susceptible to vancomycin, rifampin, and it is one of the few descriptions of the potential utility of non- β-lactams including penicillin. There was limited resistance surgical management approaches for P. acnes infections, which noted to clindamycin. Despite widespread use of the tetracy- could include a trial of antibiotic therapy prior to surgical con- cline class for acne, minocycline MICs for this study population siderations. Future, larger studies prospectively evaluating alter- were all within the expected susceptibility range. The observed native surgical and nonsurgical management approaches, oral susceptibility patterns were similar to those of other recent se- versus parenteral therapy, optimal antibiotic duration, and ap- ries of P. acnes shoulder isolates and suggest that in general, the propriate patient selection will be needed for the further optimi- broad antimicrobial susceptibility of P. acnes isolates in deep zation of the clinical management of P acnes infections. shoulder PJIs appears to be maintained [29, 39]. Acknowledgments This study does carry the limitations of a primarily descrip- We acknowledge Deborah Popoli and Qumars Roshanian (Johns Hop- tive retrospective case series, without predefined diagnostic and kins University School of Medicine, Department of Pathology) for assistance therapeutic procedures, which could bias result interpretation. with data management. Financial support. This work was supported by the Johns Hopkins Assessment of clinical outcomes was also primarily qualitative. University School of Medicine, Sherrilyn and Ken Fisher Center for Envi- However, it is accepted that the primary goal of prosthetic joint ronmental Infectious Diseases. replacement and PJI treatment is to improve quality of life by Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Con- striving for a painless and functional joint, which were the cri- flicts of Interest. teria used to define a favorable study outcome [1, 6]. No gold standard exists for PJI diagnosis. However, we adapted previ- References ously applied criteria in our case definition [1, 3, 22, 29, 30]. 1. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med 2009; 361:787–94. On retrospective review, limited specimens were obtained for 2. Kurtz S, Ong K, Lau E, et al. 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