Does a New Antibiotic Scheme Improve the Outcome of Staphylococcus aureus-Caused Acute Prosthetic Joint Infections (PJI) Treated with Debridement, Antibiotics and Implant Retention (DAIR)?

One of the most commonly used treatments for acute prosthetic joint infection (PJI) is DAIR (debridement, antibiotics and implant retention), which comprises the debridement and the retention of the implant, followed by antibiotic treatment. The efficacy of DAIR remains unclear, as the literature has demonstrated variable success rates, ranging from 26% to 92%. The Staphylococcus aureus is one of the most closely related causative microorganisms, especially with acute and late-acute PJI; it has been identified as one of the most significant predictors of DAIR failure. The current guidelines consider the use of vancomycin as the therapy of choice, but it requires the close control of possible side effects. The aim of this study is to determine if a new combination of antibiotics (a highly bactericidal initial combination followed by an antibiofilm scheme) decreases the failure of DAIR-treated acute prosthetic joint infection (PJI) caused by Staphylococcus aureus. A retrospective analysis of cases of orthopedic infections during a nine-year period (2011-2019) was performed. A total of 45 acute PJI cases caused by S. aureus were diagnosed. The results of two antibiotic schemes were compared: a novel scheme comprising 5 days of daptomycin (10 mg/kg/24 h) + cloxacillin (2 g/6 h) followed by levofloxacin (500 mg/24 h) + rifampicin (600 mg/24 h), versus a traditional, less bactericidal scheme of vancomycin (1000 mg/12 h) plus rifampicin (600 mg/24 h) or levofloxacin (500 mg/24 h) plus rifampicin (600 mg/24 h). Twenty-two out of the twenty-four patients treated with the new scheme (91.6%) were free of infection after 24.8 months of mean follow-up, whereas fourteen out of twenty-one patients (66.6%) were free of infection after 46.6 months of follow-up. This difference was statistically significant (p = 0.036). Demographic comparisons demonstrated homogeneous features, except the Charlson score, which was higher in the novel scheme group (p = 0.047). The combination of high-dose daptomycin and cloxacillin, followed by levofloxacin plus rifampicin, together with surgical treatment, shows better results when compared with other antibiotic schemes for treating acute PJI caused by S. aureus in which DAIR was performed.

Comparative In Vitro Study of Biofilm Formation and Antimicrobial Susceptibility in Gram-Negative Bacilli Isolated from Prosthetic Joint Infections.

Prosthetic joint infections (PJIs) are typically caused by microorganisms that grow in biofilms. Traditional antimicrobial susceptibility tests are based on the study of planktonic bacteria that might lead to missing the biofilm behavior and to a treatment failure. This study was designed to analyze the antimicrobial susceptibility of clinical Gram-negative bacilli (GNB) isolates from PJIs in planktonic and sessile states and the possible relationship between antimicrobial resistance and biofilm formation. A total of 46 clinical isolates from patients with PJIs (mainly hip and knee prostheses) plus three GNB ATCC isolates were studied. The Minimal Inhibitory Concentration (MIC), minimal bactericidal concentration (MBC), minimal biofilm inhibitory concentration (MBIC), and minimal biofilm eradication concentration (MBEC) were assessed using a previously published methodology. Almost all of the GNB clinical isolates tested were biofilm forming. Pseudomonas aeruginosa was the largest biofilm-forming species. A comparison of MBIC90 versus MIC90 shows an increase higher than 1- to -2-fold dilutions in most antimicrobials studied, and MBEC90 was significantly higher than MIC90, becoming resistant to all the antimicrobial drugs tested. Higher biofilm production values were obtained in antibiotic-susceptible Escherichia coli in comparison to their resistant counterparts. However, regarding the relationships between antimicrobial resistance and biofilm formation, our analysis showed that each strain differed. A high antimicrobial resistance rate was found among the GNB studied. Moreover, almost all bacterial isolates were in vitro biofilm formers. Although there was no significant association between biofilm and antibiotic resistance, multidrug-resistant isolates were found to be greater biofilm formers than non-multidrug-resistant isolates. IMPORTANCE This study is the first one to analyze a high number of isolates of Gram-negative bacilli that are the cause of prosthetic joint infection. The analysis includes biofilm development and antimicrobial susceptibility testing of both planktonic and sessile bacteria. The obtained results support the clinical knowledge about the treatment of these bacteria when biofilms are involved.

Usefulness of a Multiplex PCR Assay for the Diagnosis of Prosthetic Joint Infections in the Routine Setting.

OBJECTIVE: To evaluate the usefulness of a multiplex polymerase chain reaction (PCR) assay as a complementary tool in the diagnosis of prosthetic joint infections in the routine setting of a clinical microbiology laboratory, with a special focus on patients at high risk of culture-negative infections and high suspicion of infection. METHODS: The results obtained in the routine care setting with the use of the commercial multiplex PCR (Unyvero i60©, Curetis AG, Holzgerlingen, Germany) were retrospectively reviewed. The test was performed in samples of patients with suspected prosthetic joint infection, which were also processed for conventional diagnostic methods, including sonication of the implant when possible. Patients selected for the test were those with negative cultures after a 24-h incubation period. RESULTS: Ninety-nine PCRs were performed, 57 of which were diagnostic of infection according to 2018 MSIS criteria. Nine patients received antibiotics within the 15 days prior to the diagnostic procedure. Tested samples included synovial fluid (33), sonication fluid (56) and tissue biopsies (10). The PCR test detected microorganisms in 26 samples: including two cases of polymicrobial infection. Eleven patients were diagnosed by using PCR only. The most frequently detected microorganism in PCR was Coagulase-Negative Staphylococcus in 11 samples, followed by Staphylococcus aureus in five. One sample was positive for the bacteria universal primer, included in the 2.0 version of the kit. Only one discrepancy was detected between a negative PCR and a positive culture. One sample was also positive for a resistance marker (detection of mecA gene in a case of methicillin-resistant S. aureus infection). CONCLUSION: The incorporation of the Unyvero ITI multiple PCR technique in patients selected by clinical experts is a useful tool for the diagnosis of bone and joint infections in a routine care setting. A close clinical-microbiological collaboration improves the usefulness of this kit for the management of patients with these infections.

How to Handle Concomitant Asymptomatic Prosthetic Joints During an Episode of Hematogenous Periprosthetic Joint Infection, a Multicenter Analysis.

BACKGROUND: Prosthetic joints are at risk of becoming infected during an episode of bacteremia, especially during Staphylocococcus aureus bacteremia. However, it is unclear how often asymptomatic periprosthetic joint infection (PJI) occurs, and whether additional diagnostics should be considered. METHODS: In this multicenter study, we retrospectively analyzed a cohort of patients with a late acute (hematogenous) PJI between 2005-2015 who had concomitant prosthetic joints in situ. Patients without at least 1 year of follow-up were excluded. RESULTS: We included 91 patients with a hematogenous PJI and 108 concomitant prosthetic joints. The incident PJI was most frequently caused by Staphylococcus aureus (43%), followed by streptococci (26%) and Gram-negative rods (18%). Of 108 concomitant prosthetic joints, 13 were symptomatic, of which 10 were subsequently diagnosed as a second PJI. Of the 95 asymptomatic prosthetic joints, 1 PJI developed during the follow-up period and was classified as a "missed" PJI at the time of bacteremia with S. aureus (1.1%). Infected prosthetic joints were younger than the noninfected ones in 67% of cases, and prosthetic knees were affected more often than prosthetic hips (78%). CONCLUSIONS: During an episode of hematogenous PJI, concomitant asymptomatic prosthetic joints have a very low risk of being infected, and additional diagnostic work-up for these joints is not necessary.

Genotypic and Phenotypic Characteristics of Staphylococcus aureus Prosthetic Joint Infections: Insight on the Pathogenesis and Prognosis of a Multicenter Prospective Cohort.

BACKGROUND: Staphylococcus aureus is the leading cause of prosthetic joint infection (PJI). Beyond the antibiogram, little attention has been paid to the influence of deep microbiological characteristics on patient prognosis. Our aim was to investigate whether microbiological genotypic and phenotypic features have a significant influence on infection pathogenesis and patient outcome. METHODS: A prospective multicenter study was performed, including all S. aureus PJIs (2016-2017). Clinical data and phenotypic (agr functionality, ß-hemolysis, biofilm formation) and genotypic characteristics of the strains were collected. Biofilm susceptibility to antimicrobials was investigated (minimal biofilm eradication concentration [MBEC] assay). RESULTS: Eighty-eight patients (39.8% men, age 74.7 ±â€…14.1 years) were included. Forty-five had early postoperative infections (EPIs), 21 had chronic infections (CPIs), and 19 had hematogenous infections (HIs). Twenty (22.7%) were caused by methicillin-resistant S. aureus. High genotypic diversity was observed, including 16 clonal complexes (CCs), with CC5 being the most frequent (30.7%). agr activity was greater in EPI than CPI (55.6% vs 28.6%; P = .041). Strains causing EPI were phenotypically and genotypically similar, regardless of symptom duration. Treatment failure (36.5%) occurred less frequently among cases treated with implant removal. In cases treated with debridement and implant retention, there were fewer failures among those who received combination therapy with rifampin. No genotypic or phenotypic characteristics predicted failure, except vancomycin minimal inhibitory concentration ≥1.5 mg/L (23.1% failure vs 3.4%; P = .044). MBEC50 was >128 mg/L for all antibiotics tested and showed no association with prognosis. CONCLUSIONS: S. aureus with different genotypic backgrounds is capable of causing PJI, showing slight differences in clinical presentation and pathogenesis. No major microbiological characteristics were observed to influence the outcome, including MBEC.

Lower Success Rate of Débridement and Implant Retention in Late Acute versus Early Acute Periprosthetic Joint Infection Caused by Staphylococcus spp. Results from a Matched Cohort Study.

BACKGROUND: Surgical débridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. QUESTIONS/PURPOSES: (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? METHODS: In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. RESULTS: Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p < 0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p < 0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p < 0.001). CONCLUSIONS: Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

Orthopedic Implant-Associated Infection by Multidrug Resistant Enterobacteriaceae.

INTRODUCTION: Orthopedic implant-associated infections caused by multidrug-resistant Enterobacteriaceae are a growing challenge for healthcare providers due to their increasing incidence and the difficulties of medical and surgical treatment. MATERIAL AND METHODS: A retrospective observational study of all cases of multidrug resistant Enterobacteriaceae orthopedic implant-associated infection diagnosed in a tertiary European hospital from December 2011 to November 2017 was carried out. Clinical records were reviewed using a previously designed protocol. Data analysis was performed with IBM® SPSS®, version 22. RESULTS: 25 patients met inclusion criteria. The infected implants included 10 prosthetic joints, seven osteosyntheses, six combinations of prosthetic joint and osteosynthesis material, and two spacers. Of the multidrug resistant Enterobacteriaceae obtained on culture, 12 were extended-spectrum beta-lactamase-producing Escherichia coli, three OXA-48-producing Klebsiella pneumoniae, nine extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, and one extended-spectrum beta-lactamase-producing Proteus mirabilis. Combination antimicrobial therapy was employed in all cases but two. Overall, 16 (64%) patients underwent implant removal. The rate of infection control in the overall implant removal group was 100% compared to 33% in the implant retention group. A strong relationship between implant removal and infection control was observed (p = 0.001). DISCUSSION: Implant removal is strongly associated with infection control. However, in some cases, patient age and comorbidity contraindicate hardware extraction. Potential objectives for future studies should be geared towards targeting the population in which debridement, antibiotic therapy, and implant retention can be used as a first-line therapeutic strategy with a reasonable probability of achieving infection control.

Clinical outcome and risk factors for failure in late acute prosthetic joint infections treated with debridement and implant retention.

OBJECTIVES: Debridement, antibiotics and implant retention (DAIR) is the recommended treatment for all acute prosthetic joint infections (PJI), but its efficacy in patients with late acute (LA) PJI is not well described. METHODS: Patients diagnosed with LA PJI between 2005 and 2015 were retrospectively evaluated. LA PJI was defined as the development of acute symptoms (≤ 3 weeks) occurring ≥ 3 months after arthroplasty. Failure was defined as: (i) the need for implant removal, (ii) infection related death, (iii) the need for suppressive antibiotic therapy and/or (iv) relapse or reinfection during follow-up. RESULTS: 340 patients from 27 centers were included. The overall failure rate was 45.0% (153/340). Failure was dominated by Staphylococcus aureus PJI (54.7%, 76/139). Significant independent preoperative risk factors for failure according to the multivariate analysis were: fracture as indication for the prosthesis (odds ratio (OR) 5.4), rheumatoid arthritis (OR 5.1), age above 80 years (OR 2.6), male gender (OR 2.0) and C-reactive protein > 150 mg/L (OR 2.0). Exchanging the mobile components during DAIR was the strongest predictor for treatment success (OR 0.35). CONCLUSION: LA PJIs have a high failure rate. Treatment strategies should be individualized according to patients' age, comorbidity, clinical presentation and microorganism causing the infection.

Evaluation of the use of sonication of retrieved implants for the diagnosis of prosthetic joint infection in a routine setting.

In order to evaluate the usefulness of sonication of retrieved implants for the diagnosis of prosthetic joint infection (PJI) in a large group of patients in a routine setting, we designed a 3-year retrospective study. Patients were classified into two groups: those meeting the clinical criteria of PJI and those that did not (control group). Two hundred patients and 276 samples were included. The types of infection were early (n = 44), delayed (n = 53), positive intraoperative cultures (n = 13) and late-acute (n = 8). The culture sensitivities of sonicate fluid, periprosthetic tissue, synovial fluid and combination of periprosthetic tissue and/or synovial fluid were 69.5, 52.8, 54.8 and 60.2%, respectively. The specificities were 97.6, 90.3, 93.0 and 89.9%, respectively. Sonicate fluid culture of implants was more sensitive than peri-implant tissue, synovial fluid and combination of periprosthetic tissue and/or synovial fluid for all infection types, though it was especially useful in delayed infection: 91.3% vs. 60.0% (p = 0.0015), 63.2% (p = 0.0005) and 66.7% (p = 0.0001), respectively. When sonicate fluid culture of implants was performed in addition to conventional cultures, the sensitivity increased significantly in total (from 60.2 to 77.1%) and delayed PJI (from 45.1 to 71.7%). On the other hand, for early PJI, sonicate fluid culture of prosthesis was not superior to conventional diagnostic methods.

Evaluation of a commercial multiplex PCR (Unyvero i60(R)) designed for the diagnosis of bone and joint infections using prosthetic-joint sonication / Evaluación de una PCR múltiple comercial (Unyvero i60(C)) diseñada para el diagnóstico de infecciones osteoarticulares utilizando prótesis articulares sonicadas

BACKGROUND: The development of sonication protocols over the last few years has improved the sensitivity of conventional cultures for the diagnosis of prosthetic-joint infection (PJI). However, the development of a new, specifically designed kit for the molecular diagnosis of PJI could provide a major improvement in this field. METHODS: Prostheses retrieved from patients who underwent implant removal from May 2014 to May 2015 were sent for culture, and processed according to a previously defined protocol that included sonication. Furthermore, 180 microlitres of sonication fluid were used to carry out the multiplex PCR test (Unyvero i60 system®). A comparison of the sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, was performed. The study was approved by the Clinical Research Ethics Committee. RESULTS: The analysis included 88 prostheses from 68 patients (1.29 prostheses/patient). The type of prostheses studied were knee (n=55), total hip (n=26), partial hip (n=5), and shoulder (n=2). Twenty-nine patients were diagnosed with a PJI (15 delayed, 12 acute, and 2 haematogenous infections). In 24 cases, the result of the PCR was positive, all but 1 corresponding to patients with clinical criteria of PJI. Nine resistance mechanisms were detected from 5 samples. The Unyvero i60 system® showed slightly better results than traditional culture in terms of specificity and PPV. CONCLUSIONS: The Unyvero i60 system® may play a role in rapid diagnosis of PJI, due to its high specificity and PPV. However, despite these results, cultures have to be performed to detect organisms not detected by the system

INTRODUCCIÓN: El desarrollo de la sonicación durante los pasados años ha incrementado la sensibilidad de los cultivos convencionales para el diagnóstico de Infecciones de Prótesis Articulares (IPA). Sin embargo, el desarrollo de un nuevo kit, diseñado específicamente para el diagnóstico de las IPA podría suponer un avance significativo en este campo. MÉTODOS: Todas las prótesis retiradas de pacientes entre mayo 2014 y mayo 2015 fueron enviadas para cultivo mediante un protocolo de procesamiento que incluye la sonicación del implante. Además, se emplearon 180 microlitros del líquido de sonicado en la realización de una PCR múltiple (Unyvero i60®). Se realizó una comparación de la sensibilidad, especificidad, valor predictivo positivo (VPP) y negativo (VPN). El estudio fue aprobado por el Comité de Ética en Investigación Clínica. RESULTADOS: Se analizaron 88 prótesis de 68 pacientes (1,29 prótesis/paciente). Las prótesis estudiadas fueron rodillas (n=55), total de cadera (n=26), parcial de cadera (n=5), y hombro (n=2). Veintinueve pacientes fueron diagnosticados de IPA (15 crónicas, 12 agudas y 2 hematógenas). En 24 casos, el resultado de la PCR fue positivo, siendo todas menos 1 de estas de pacientes con criterios de IPA. Se detectaron además 9 mecanismos de resistencia en 5 muestras. El sistema Unyvero i60® mostró resultados ligeramente superiores al cultivo tanto en especificidad como en VPP. CONCLUSIONES: El sistema Unyvero i60® puede tener un papel en el diagnóstico rápido de IPA debido a su elevada especificidad y VPP. Sin embargo, a pesar de estos resultados, debe realizarse cultivo para detectar organismos no detectados por el sistema

Evaluation of a commercial multiplex PCR (Unyvero i60®) designed for the diagnosis of bone and joint infections using prosthetic-joint sonication.

BACKGROUND: The development of sonication protocols over the last few years has improved the sensitivity of conventional cultures for the diagnosis of prosthetic-joint infection (PJI). However, the development of a new, specifically designed kit for the molecular diagnosis of PJI could provide a major improvement in this field. METHODS: Prostheses retrieved from patients who underwent implant removal from May 2014 to May 2015 were sent for culture, and processed according to a previously defined protocol that included sonication. Furthermore, 180 microlitres of sonication fluid were used to carry out the multiplex PCR test (Unyvero i60 system®). A comparison of the sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, was performed. The study was approved by the Clinical Research Ethics Committee. RESULTS: The analysis included 88 prostheses from 68 patients (1.29 prostheses/patient). The type of prostheses studied were knee (n=55), total hip (n=26), partial hip (n=5), and shoulder (n=2). Twenty-nine patients were diagnosed with a PJI (15 delayed, 12 acute, and 2 haematogenous infections). In 24 cases, the result of the PCR was positive, all but 1 corresponding to patients with clinical criteria of PJI. Nine resistance mechanisms were detected from 5 samples. The Unyvero i60 system® showed slightly better results than traditional culture in terms of specificity and PPV. CONCLUSIONS: The Unyvero i60 system® may play a role in rapid diagnosis of PJI, due to its high specificity and PPV. However, despite these results, cultures have to be performed to detect organisms not detected by the system.

Clinical and microbiological characteristics of patients with septic arthritis: A hospital-based study.

BACKGROUND: To determine the clinical and epidemiological characteristics, etiology, underlying conditions, and outcomes of patients with primary septic arthritis and no prosthetic joints at a university hospital. METHODS: A retrospective study was performed between 2005 and 2012. Records from the Microbiology Department were reviewed, and patients with a positive culture of synovial fluid or biopsy were selected for the study. Clinical charts were reviewed using a designed protocol. RESULTS: 41 patients were diagnosed with septic arthritis with a positive culture. Most were diagnosed with monoarticular (85.37%) and monomicrobial (92.68%) arthritis. The most commonly involved joint was the knee (34.15%). The most frequent underlying conditions were hypertension and diabetes mellitus. Staphylococcus aureus was the most common pathogen (58.54%). Two cases of chronic arthritis, both caused by Mycobacterium tuberculosis were detected. The most frequently used antibiotic combinations were cloxacillin + ciprofloxacin and vancomycin + ciprofloxacin. Surgical treatment included needle aspiration, open joint debridement, or arthroscopic techniques. Twelve cases had a poor outcome (destructive articular disease), and 3 patients died from staphylococcal sepsis. CONCLUSIONS: In our hospital, septic arthritis is primarily acute, monoarticular, and monomicrobial; affects higher joints, is caused by S. aureus, and occurs in adult patients with underlying diseases. Outcome is good in most patients, although more than 25% of cases had articular sequels.

Aspirin prevents Escherichia coli lipopolysaccharide- and Staphylococcus aureus-induced downregulation of endothelial nitric oxide synthase expression in guinea pig pericardial tissue.

The aim was to analyze whether pericardial tissue expresses endothelial NO synthase (eNOS) protein and to determine the presence of cytosolic proteins that bind to eNOS mRNA. The effect of aspirin on the above-mentioned parameters was also analyzed. eNOS protein was expressed in pericardial tissue from male guinea pigs. Escherichia coli lipopolysaccharide (LPS, 10 microgram/mL) and Staphylococcus aureus endotoxin (SA, 10 microgram/mL) reduced eNOS protein expression and shortened the half-life of the eNOS messenger. Under basal conditions, cytosolic extracts from pericardial samples bound to the 3'-untranslated region (3'-UTR) of eNOS mRNA, which was enhanced by LPS and SA. Proteinase K fully prevented the binding of cytosolic pericardial extracts to 3'-UTR of eNOS mRNA, suggesting the involvement of proteins that were further characterized as 60- and 51-kDa proteins. Aspirin (1 to 10 mmol/L) restored eNOS expression in either LPS- and SA-stimulated pericardial samples and reduced the binding activity of the pericardial cytosolic proteins to 3'-UTR of eNOS mRNA. Indomethacin also reduced the downregulation of eNOS by LPS and diminished the binding activity of the cytosolic proteins, although higher doses of indomethacin than of aspirin were needed to improve these parameters. In conclusion, eNOS protein is expressed in guinea pig pericardial tissue. LPS and SA stimulate the binding activity of pericardial cytosolic proteins to 3'-UTR of eNOS mRNA and reduce eNOS protein expression. High doses of aspirin and indomethacin protect eNOS protein expression and reduce the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting an inverse association between the presence of these cytosolic proteins and eNOS expression.