Effect of Preoperative Antibiotic Therapy on Operative Culture Yield for Diagnosis of Native Joint Septic Arthritis.

BACKGROUND: Native joint septic arthritis (NJSA) is definitively diagnosed by a positive Gram stain or culture, along with supportive clinical findings. Preoperative antibiotics are known to alter synovial fluid cell count, Gram stain and culture results and are typically postponed until after arthrocentesis to optimize diagnostic accuracy. However, data on the impact of preoperative antibiotics on operative culture yield for NJSA diagnosis are limited. METHODS: We retrospectively reviewed adult cases of NJSA who underwent surgery at Mayo Clinic facilities from 2012-2021 to analyze the effect of preoperative antibiotics on operative culture yield through a paired analysis of preoperative culture (POC) and operative culture (OC) results using logistic regression and generalized estimating equations. RESULTS: Two hundred ninety-nine patients with NJSA affecting 321 joints were included. Among those receiving preoperative antibiotics, yield significantly decreased from 68.0% at POC to 57.1% at OC (p < .001). In contrast, for patients without preoperative antibiotics there was a non-significant increase in yield from 60.9% at POC to 67.4% at OC (p = 0.244). In a logistic regression model for paired data, preoperative antibiotic exposure was more likely to decrease OC yield compared to non-exposure (OR = 2.12; 95% CI = 1.24-3.64; p = .006). Within the preoperative antibiotic group, additional antibiotic doses and earlier antibiotic initiation were associated with lower OC yield. CONCLUSION: In patients with NJSA, preoperative antibiotic exposure resulted in a significant decrease in microbiologic yield of operative cultures as compared to patients in whom antibiotic therapy was held prior to obtaining operative cultures.

Phage Therapy as a Novel Therapeutic for the Treatment of Bone and Joint Infections.

Solutions for bone and joint infection (BJI) are needed where conventional treatments are inadequate. Bacteriophages (phages) are naturally occurring viruses that infect bacteria and have been harnessed for refractory bone and joint infections (BJI) in many case reports. Here we examine the safety and efficacy of English-language published cases of BJI since 2010 with phage therapy. From 33 reported cases of BJI treated with phage therapy, 29 (87%) achieved microbiological or clinical success, 2 (5.9%) relapsed with the same organisms, and 2 (5.9%) with a different organism. Of these 4 relapses, all but 1 had eventual clinical resolution with additional surgery or phage treatments. Eight out of 33 cases (24%) reported mild, transient adverse events with no serious events reported. Further work is needed to understand the true efficacy of phages and the role of phages in BJI. Opportunities lay ahead for thoughtfully designed clinical trials adapted to individualized therapies.

A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes.

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. RESULTS: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. CONCLUSIONS: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

Outcomes and risk factors for failure after débridement, antibiotics, and implant retention for elbow periprosthetic joint infection.

BACKGROUND: Evidence for the management of periprosthetic joint infection (PJI) after total elbow arthroplasty is sparse, particularly in regard to débridement, antibiotics, and implant retention (DAIR). This study explored the outcomes of DAIR and analyzed risk factors for failure. METHODS: A retrospective cohort study of patients 18 years or older diagnosed with elbow PJI and managed with DAIR between January 1, 2003, and December 31, 2018, at a single institution was performed. Twenty-six elbows met the inclusion criteria during the study period. All DAIR procedures included in this study represented an attempt to manage an acute PJI with surgical irrigation and débridement without removal of the elbow arthroplasty components, followed by long-term systemic antimicrobial therapy. DAIR failure was defined as recurrence of PJI, unplanned re-operation for infection, or death secondary to infection. A Cox proportional hazards model was used to identify possible risk factors for failure. RESULTS: DAIR failed in 17 cases of elbow PJI with a failure rate of 65% at 2 years (95% confidence interval: 41.3%-79.6%). The median time to failure from DAIR was 43 days (interquartile range: 27-114). We found that DAIR failed in all cases with sinus tracts or negative cultures. The group with favorable outcomes had a shorter median duration of symptoms (5 vs. 18 days, P = .65) and a higher proportion of monomicrobial infections (58.8% vs. 88.9%, P = .19) compared to those with unfavorable outcomes. However, with the numbers available, none of the possible risk factors analyzed for association with failure reached statistical significance. CONCLUSION: DAIR for elbow PJI was associated with high rates of failure. Possible risk factors for failure may include the presence of sinus tract, longer duration of symptoms, and culture-negative infection. Although the relatively low morbidity of DAIR compared with total elbow arthroplasty implant resection for a one-stage or two-stage reimplantation is attractive, patients considered for DAIR must know that the chance of success is limited to approximately 35%.

Considerations for the Use of Phage Therapy in Clinical Practice.

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.

Enhancing Diagnostics in Orthopedic Infections.

Accurate diagnosis of orthopedic infection is crucial in guiding both antimicrobial therapy and surgical management in order to optimize patient outcomes. A variety of microbiological and nonmicrobiological methods are used to establish the presence of a musculoskeletal infection. In this minireview, we examine traditional culture-based and newer molecular methodologies for pathogen detection, as well as systemic and localized assays to assess host response to maximize diagnostic yield.

Safety and Tolerability of Fluoroquinolones in Patients with Staphylococcal Periprosthetic Joint Infections.

BACKGROUND: Fluoroquinolones (FQs) are known to be accompanied by significant risks. However, the incidence of adverse events (ADEs) resulting in unplanned drug discontinuation when used for periprosthetic joint infections (PJIs) is currently unknown. METHODS: This study included 156 patients over the age of 18 treated for staphylococcal PJI with debridement, antibiotics, and implant retention between 1 January 2007 and 21 November 2019. Of the 156 patients, 64 had total hip arthroplasty (THA) and 92 had total knee arthroplasty (TKA) infections. The primary outcome was rate of unplanned drug discontinuation. Secondary outcomes included incidence of severe ADEs, unplanned rifamycin discontinuation, mean time to unplanned regimen discontinuation, and all-cause mortality. RESULTS: Overall, unplanned drug discontinuation occurred in 35.6% of patients in the FQ group and 3% of patients in the non-FQ group. The rate of unplanned discontinuation of FQ regimens as compared with non-FQ regimens was 27.5% vs 4.2% (P = .021) in THA infections and 42% vs 2.4% (P < .001) in TKA infections. There was no significant difference in severe ADEs between FQ and non-FQ regimens in both THA and TKA infections. The overall rate of nonsevere ADEs in FQ compared with non-FQ regimens was 43.3% vs 6.1% (P < .001). FQs were associated with tendinopathy, myalgia, arthralgia, and nausea. CONCLUSIONS: A significantly higher rate of unplanned drug discontinuation was associated with FQ as compared with non-FQ regimens. This provides a real-world view of the implications of FQ-related ADEs on unplanned discontinuation when used in prolonged durations for the management of staphylococcal PJIs.

Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity.

BACKGROUND: Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention. METHODS: The patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining. RESULTS: Phage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.

Synchronous Periprosthetic Joint Infections: High Mortality, Reinfection, and Reoperation.

BACKGROUND: Synchronous periprosthetic joint infections (PJIs) are a catastrophic complication with potentially high mortality. We aimed to report mortality, risk of reinfection, revision, reoperation, and implant survivorship after synchronous PJIs. METHODS: We identified 34 patients treated for PJI in more than one joint within a single 90-day period from 1990 to 2018. PJIs involved bilateral knee arthroplasty (27), bilateral hip arthroplasty (4), 1 knee arthroplasty and 1 elbow arthroplasty (1), 1 knee arthroplasty and 1 shoulder arthroplasty (1), and bilateral hip and knee arthroplasty (1). Irrigation and debridement with component retention was performed in 23 patients, implant resection in 10 patients, and a combination of irrigation and debridement with component retention and implant resection in 1 patient. A competing risk model was used to analyze implant survivorship, and Kaplan-Meier survival was used for patient mortality. Mean follow-up was 6 years. RESULTS: Mortality was high at 18% at 30 days and 27% at 1 year. The 1-year cumulative incidence of any reinfection was 13% and 27% at 5 years. The 1-year cumulative incidence of any revision or implant removal was 6% and 20% at 5 years. The 1-year cumulative incidence of unplanned reoperation was 25% and 35% at 5 years. Rheumatoid arthritis was associated with increased risk of mortality (HR 7, P < .01), as was liver disease (HR 4, P = .02). CONCLUSION: In the largest series to date, patients with synchronous PJIs had a high 30-day mortality rate of 18%, and one-fourth underwent unplanned reoperation within the first year.

Phage Therapy for Cardiac Implantable Electronic Devices and Vascular Grafts: A Targeted Literature Review.

Infections of cardiac implantable electronic devices (CIEDs) and vascular grafts are some of the most dreaded complications of these otherwise life-saving devices. Many of these infections are not responsive to conventional treatment, such as systemic antibiotics and surgical irrigation and debridement. Therefore, innovative strategies to prevent and manage these conditions are warranted. Among these, there is an increasing interest in phages as a therapeutical option. In this review, we aim to collect the available evidence for the clinical application of phage therapy for CIED and vascular graft infections through literature research. We found 17 studies for a total of 34 patients. Most of the indications were left ventricular assist device (LVAD) (n = 20) and vascular graft infections (n = 7). The bacteria most often encountered were Staphylococcus aureus (n = 18) and Pseudomonas aeruginosa (n = 16). Clinical improvements were observed in 21/34 (61.8%) patients, with microbiological eradication in 18/21 (85.7%) of them. In eight cases, an adverse event related to phage therapy was reported. Phage therapy is a promising option for difficult-to-treat CIED and vascular graft infections by means of an individualized approach. Clinical trials and expanded access programs for compassionate use are needed to further unveil the role of phage therapy in clinical application.

No differences in outcomes with stopping or continuing antibiotic suppression in periprosthetic joint infections.

The data on long-term antibiotic use following debridement, antibiotics, and implant retention (DAIR) for treatment of periprosthetic joint infections are limited. In this single-center retrospective study, we show that patients with eventual cessation of antibiotic suppression after DAIR had similar outcomes to those who remained on chronic antibiotic suppression.

Role of Routine Suppressive Antibiotic Therapy After Debridement, Antibiotics, and Implant Retention for Acute Periprosthetic Joint Infections.

Background: The first-line management strategy for acute periprosthetic joint infections (PJIs) is debridement, antibiotics, and implant retention (DAIR). Suppressive antibiotic therapy (SAT) after DAIR is proposed to improve outcomes, yet its efficacy remains under scrutiny. Methods: We conducted a multicenter retrospective study in patients with acute PJI of the hip or knee who were treated with DAIR in centers from Europe and the United States. We analyzed the effect of SAT using a Cox model landmarked at 12 weeks. The primary covariate of interest was SAT, which was analyzed as a time-varying covariate. Patients who experienced treatment failure or were lost to follow-up within 12 weeks were excluded from the analysis. Results: The study included 510 patients with 66 treatment failures with a median follow-up of 801 days. We did not find a statistically significant association between SAT and treatment failure (hazard ratio, 1.37; 95% CI, .79-2.39; P = .27). Subgroup analyses for joint, country cohort, and type of infection (early or late acute) did not show benefit for SAT. Secondary analysis of country cohorts showed a trend toward benefit for the US cohort (hazard ratio, 0.36; 95% CI, .11-1.15; P = .09), which also had the highest risk of treatment failure. Conclusions: The utility of routine SAT as a strategy for enhancing DAIR's success in acute PJI remains uncertain. Our results suggest that SAT's benefits might be restricted to specific groups of patients, underscoring the need for randomized controlled trials. Identifying patients most likely to benefit from SAT should be a priority in future studies.

Clinical phage microbiology: a narrative summary.

BACKGROUND: Although phage therapy has been in existence for a century, a recent resurgence in interest has occurred because of the continued emergence of antimicrobial resistance and the rising use of indwelling medical devices, resulting in biofilm-associated infections, for which conventional antibiotics are of limited use. Despite this, the clinical successes have been inconsistent because of multiple reasons, including (1) the narrow host range of phages, (2) challenges with concentrating phages at the site of infection, (3) development of resistance of bacteria to phages and (4) immune neutralization. Microbiologic assays have the potential to help guide the course of clinical therapy and improve outcomes. Methods developed decades ago remain the mainstay of phage diagnostics and recently, newer diagnostics are closing the gap needed to further advance clinical phage therapy. OBJECTIVES: To review the current state of clinical phage microbiology and identify gaps. SOURCES: A PubMed search was performed using the terms "phage microbiology", "phage susceptibility test", "phage host range", "phage biofilm", and "phage therapeutic monitoring". CONTENT: Phage susceptibility testing, biofilm assays, phage-antibiotic combination testing, therapeutic drug monitoring, and immune monitoring assays are the current foundation for clinical phage diagnostics. Standardization of these assays and better understanding as to if and how they should be used in terms of clinical management of patients receiving phage therapy is needed. IMPLICATIONS: A substantial gap between in vitro studies and in vivo outcomes indicates that further work is needed in phage pharmacokinetics to accurately assay phage particles at the site of infection; recapitulate in vivo biofilm; capture the complex interactions between phages and antibiotics, phages and their target bacteria, among phages in a cocktail, and with the superhost immune system.

Chronic Polymicrobial Infectious Melanonychia Striata.

CASE: A 62-year-old man presented with a 10-year history of isolated melanonychia striata of his dominant thumb. Surgical biopsy ruled out subungual melanoma but revealed foreign plant material causing chronic infectious melanonychia from multiple pathogens, including Pseudomonas aeruginosa, Escherichia coli, and Candida spp. After removal of the nail plate and thorough debridement, the melanonychial streak resolved completely at 12 months of follow-up. CONCLUSION: Bacterial infection is a rarely reported cause of melanonychia, and in addition to surgical pathologic specimens, intraoperative fungal and bacterial cultures should always be obtained for accurate diagnosis of melanonychia striata.

Chronic Q fever presenting as bilateral extensor tenosynovitis: a case report and review of the literature.

Musculoskeletal manifestations of Coxiella burnetii are rare. We describe an elderly, immunosuppressed male with bilateral Coxiella burnetii extensor tenosynovitis treated with incision and debridement and chronic doxycycline and hydroxychloroquine. Additionally, disease etiology, risk factors, pertinent features of the history, testing modalities, and treatment strategies of musculoskeletal Q fever are reviewed.

Defeating the Hidden Foe: Antibiotic Therapy and Clinical Outcomes of Cutibacterium acnes Spinal Implant Infections.

Background: Cutibacterium acnes can cause spinal implant infections. However, little is known about the optimal medical management and outcomes of C. acnes spinal implant infections (CSII). Our study aims to describe the management of patients with CSII and evaluate the clinical outcomes. Methods: We performed a retrospective cohort study of patients aged 18 years or older who underwent spinal fusion surgery with instrumentation between January 1, 2011, and December 31, 2020, and whose intraoperative cultures were positive for C. acnes. The primary outcome was treatment failure based on subsequent recurrence, infection with another organism, or unplanned surgery secondary to infection. Results: There were 55 patients with a median follow-up (interquartile range) of 2 (1.2-2.0) years. Overall, there were 6 treatment failures over 85.8 total person-years, for an annual rate of 7.0% (95% CI, 2.6%-15.2%). Systemic antibiotic treatment was given to 74.5% (n = 41) of patients for a median duration of 352 days. In the subgroup treated with systemic antibiotics, there were 4 treatment failures (annual rate, 6.3%; 95% CI, 1.7%-16.2%), all of which occurred while on antibiotic therapy. Two failures occurred in the subgroup without antibiotic treatment (annual rate, 8.8%; 95% CI, 1.1%-31.8%). Conclusions: Our study found that the estimated annual treatment failure rate was slightly higher among patients who did not receive antibiotics. Of the 6 failures observed, 4 had recurrence of C. acnes either on initial or subsequent treatment failures. More studies are warranted to determine the optimal duration of therapy for CSII.

Sex-specific analysis of clinical features and outcomes in staphylococcal periprosthetic joint infections managed with two-stage exchange arthroplasty.

Background: Differences in susceptibility and response to infection between males and females are well established. Despite this, sex-specific analyses are under-reported in the medical literature, and there is a paucity of literature looking at differences between male and female patients with periprosthetic joint infection (PJI). Whether there are sex-specific differences in presentation, treatment tolerability, and outcomes in PJI has not been widely evaluated. Methods: We undertook a retrospective case-matched analysis of patients with staphylococcal PJI managed with two-stage exchange arthroplasty. To control for differences other than sex which may influence outcome or presentation, males and females were matched for age group, causative organism category (coagulase-negative staphylococci vs. Staphylococcus aureus), and joint involved (hip vs. knee). Results: We identified 156 patients in 78 pairs of males and females who were successfully matched. There were no significant baseline differences by sex, except for greater use of chronic immunosuppression among females (16.4 % vs. 4.1 %; p = 0.012 ). We did not detect any statistically significant differences in outcomes between the two groups. Among the 156 matched patients, 16 recurrent infections occurred during a median follow-up time of 2.9 (IQR 1.5-5.3) years. The 3-year cumulative incidence of relapse was 16.1 % for females, compared with 8.8 % for males ( p = 0.434 ). Conclusions: Success rates for PJI treated with two-stage exchange arthroplasty are high, consistent with previously reported literature. This retrospective case-matched study did not detect a significant difference in outcome between males and females with staphylococcal PJI who underwent two-stage exchange arthroplasty.