Superficial Surgical Site Infections in Primary Total Joint Arthroplasty: A Retrospective Analysis of Topical Anti-Biofilm Therapy.

Introduction Surgical site infections (SSI) following orthopedic procedures can cause significant morbidity and mortality, particularly in total joint arthroplasty. Biofilm formation in surgical wounds has made it difficult to prevent and treat these infections. SURGX® Antimicrobial Wound Gel (Next Science, Jacksonville, Florida, USA) was developed to disrupt biofilm formation but has not been evaluated in prophylactic use in total joint arthroplasty to prevent superficial SSI. Methods A retrospective chart review was performed at a single institution comparing the rate of SSI in patients undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). SSI data were collected from patients with standard postoperative dressings (Group A: Control) and patients with SURGX® applied as part of a standardized dressing following THA/TKA (Group B: Study). Rates of SSI were compared.  Results SURGX® was administered to 120 patients, including 91 TKAs and 29 THAs. The overall infection rate in this cohort was 2.5%. No superficial site infections developed. The control group constituted 566 patients, with 386 TKAs and 180 THAs. The infection rate was 1.24%, which included one superficial infection. Binary logistic regression did not show different odds of developing infections with the use of SURGX® (OR = 2.23, 95% CI: 0.54-9.13, p = 0.27). Conclusion In our small retrospective study, Next Science SURGX® Antimicrobial Wound Gel did not demonstrate a statistically significant difference in the rate of superficial SSI in total joint arthroplasty; however, Group B did not have any superficial SSI.

Treatment of Open Traumatic Medial Malleolus Bone Loss With Osteochondral Allograft: A Case Report.

Osteochondral damage to the ankle joint can be a difficult problem to manage in a young active patient. There are several described surgical treatments ranging from cartilage repair techniques to arthrodesis and ankle replacement. In this case, we present a 28-year-old male who sustained a right type IIIA open medial malleolus fracture following an all-terrain vehicle crash. After sharp debridement, the clinical decision was made to treat the patient with an osteochondral allograft. At one- and two-year post-allograft reconstruction, radiographs demonstrated good incorporation of the graft. The patient was ambulating with no pain or assistive devices. Our case report specifically describes the successful treatment of a traumatic medial malleolus ankle fracture with bone loss using an osteochondral allograft in a young active patient.

Patient-reported dissatisfaction following second side in staged bilateral total knee arthroplasty: A systematic review.

BACKGROUND: Around one third of patients who undergo total knee arthroplasty (TKA) will eventually have the contralateral knee replaced. Overall patient satisfaction after staged bilateral total knee arthroplasty procedures performed on different days is reportedly similar to unilateral TKA. Nevertheless, in our anecdotal experience patients often report less satisfying outcomes following the second side. A cursory review of available literature tended to confirm that observation. We sought therefore to consolidate all of the available data on this issue to further investigate this phenomenon. AIM: To consolidate available published data revealing satisfaction scores among patients following staged bilateral TKA, and to evaluate the phenomenon of less satisfying results following TKA2. METHODS: A systematic review of available literature reporting on satisfaction with TKA1 and TKA2 after staged bilateral knee arthroplasty was undertaken using PubMed, Google Scholar, and Embase. From 427 records, five full-length articles met criteria for inclusion in the meta-analysis. The data were then extracted and assessed on the basis of the Reference Citation Analysis (https://www.referencecitationanalysis.com/). RESULTS: A total of 1889 patients with an average age of 68 (range: 38-92) underwent staged bilateral TKA with outcomes reported at 1 year following each TKA with a mean 21.9 mo between surgeries (range: 2 d to 14.5 years). Overall satisfaction with both knees was 83.70% (1581) and dissatisfaction with both knees was 2.75% (52). In the remaining 13.56% (256) who were dissatisfied with one side, 61.0% were dissatisfied with TKA2, and 39.0% were dissatisfied with TKA1. Patient-reported outcome scores for TKA2 were frequently lower than TKA1 even in patients reporting overall satisfaction with both knees. CONCLUSION: At 1-year follow-up, there was a 50% greater risk of dissatisfaction with TKA2 among the 13.56% of patients reporting dissatisfaction in one knee after staged bilateral TKA. Whether the interval between procedures or long-term follow-up changes these results requires further investigation.

Successful Surgical Repair of Acute Quadriceps Tendon Rupture Utilizing Cortical Button Fixation: A Case Report.

BACKGROUND Timely diagnosis and surgical treatment are often needed to restore function of the extensor mechanism after rupture of the quadriceps tendon. Several techniques for quadriceps tendon repair have been reported, including suture anchors and bone tunnels. Cortical button fixation, or the use of an adjustable cortical fixation device, is a local and biomechanically strong internal brace technique used to treat ligament and tendon injuries. This report is of a 69-year-old man who experienced a quadriceps tendon rupture while golfing and underwent a successful surgical repair using cortical button fixation. CASE REPORT A 69-year-old man sustained an injury after slipping while golfing. He had immediate left knee pain and inability to bear weight. Radiographs demonstrated patella baja with an acute superior pole avulsion fracture of the patella, consistent with rupture of the quadriceps tendon. Surgical repair was discussed. Technique: After soft tissue debridement, the quadriceps tendon was debrided from the frayed and edematous edges. Two Krackow-type stitches were placed with #2 Fibertape and passed through 2 cortical buttons. Two bone tunnels were drilled from the superior to the inferior poles of the patella, bicortically. The cortical button was passed and appropriately tensioned. CONCLUSIONS Although acute quadriceps tendon rupture is commonly treated with transosseous suture repair and suture anchor repair, this report demonstrates that cortical button fixation was a successful procedure with strong biomechanical properties, resulting in the early return of function and range of motion.

End-Stage Tibiotalar Osteoarthritis and Chronic Strontium Toxicity.

Metal toxicity due to environmental sources or orthopedic implants has been a primary focus in recent literature. Specifically, in orthopedics, total joint arthroplasty regarding metal-on-metal articulation with cobalt-chromium articulation has adverse local and systemic effects. In particular, strontium toxicity is less known metal toxicity that can cause many systemic effects such as severe osteoporosis. This is the first reported case of strontium toxicity and end-stage tibiotalar osteoarthritis. We present a case of a 68-year-old female with bilateral ankle pain and deformity that were refractory to conservative measures, including physical therapy and anti-inflammatory medications. She was diagnosed with bilateral osteoarthritis and osteoporosis secondary to strontium toxicity by exclusion after extensive workup with a multi-disciplinary approach. The patient pursued conservative measures with ankle-foot orthosis, physical therapy, and anti-inflammatory medications. After the failure of conservative measures with over two years of follow-up, we recommended operative intervention to improve function and pain with staged bilateral tibiotalocalcaneal fusions utilizing an intramedullary device. Since she is moving out of state, she chose to pursue operative intervention at a different institution in order to establish long-term follow-up. The patient was placed on teriparatide for her osteoporosis secondary to strontium toxicity. Clinicians should be aware of strontium toxicity and its systemic effects and take a multi-disciplinary approach to treatment for optimal management.

Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via both Nonobligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus.

Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC50) for BCV and a 1.9-fold increased EC50 for CDV; thus, these results confirmed that viral resistance to BCV and CDV can be attributed to mutations in the viral Pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA Pol and that their antiviral activity may occur via both (nonobligate) chain termination and (at high concentration) direct inhibition of AdV5 Pol activity.

Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial.

Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.

Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-α) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy.

Allele-specific real-time PCR system for detection of subpopulations of genotype 1a and 1b hepatitis C NS5B Y448H mutant viruses in clinical samples.

The Y448H mutation in NS5B has been selected by GS-9190 as well as several benzothiadiazine hepatitis C virus (HCV) polymerase inhibitors in vitro and in vivo. However, the level and the evolution kinetics of this resistance mutation prior to and during treatment are poorly understood. In this study, we developed an allele-specific real-time PCR (AS-PCR) assay capable of detecting Y448H when it was present at a level down to 0.5% within an HCV population of genotype 1a or 1b. No Y448H mutation was detected above the assay cutoff of 0.5% in genotype 1b-infected Con-1 replicons prior to in vitro treatment. However, the proportion of replicons with the Y448H mutation rapidly increased in a dose-dependent manner upon treatment with GS-9190. After 3 days of treatment, 1.2%, 6.8%, and >50% of the replicon population expressed Y448H with the use of GS-9190 at 1, 10, and 20 times its 50% effective concentration, respectively. In addition, plasma from 65 treatment-naïve HCV-infected patients (42 and 23 with genotype 1a and 1b, respectively) was tested for the presence of Y448H by AS-PCR and population sequencing. As expected, all patient samples were wild type at NS5B Y448 by population sequencing. AS-PCR results were obtained for 62/65 samples tested, with low levels of Y448H ranging from 0.5% to 3.0% detected in 5/62 (8%) treatment-naïve patient samples. These findings suggest the need for combination therapy with HCV-specific inhibitors to avoid viral rebound of preexisting mutant HCV.

Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.

In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.

Development of a replicon-based phenotypic assay for assessing the drug susceptibilities of HCV NS3 protease genes from clinical isolates.

Hepatitis C virus (HCV) protease inhibitors targeting HCV NS3 can efficiently suppress HCV replication. However, the selection of resistance has been observed both in vitro and in vivo. Here, we describe a new method for efficient analysis of the drug susceptibility of the NS3 protease genes from patient isolates. Luciferase-reporter 1b replicon shuttle vectors that allow cloning of either the HCV full-length NS3/4A gene or the NS3 protease domain gene only were created. Initially, chimeric replicons carrying patient-derived full-length NS3/4A failed to replicate in cell culture. However, the poor replication efficiency of the NS3/4A shuttle vector was enhanced by approximately 100-fold when the NS3 helicase domains of clinical isolates were substituted for that of the 1b Con1 lab strain. Chimeric replicons carrying only the patient-derived NS3 protease domains replicated at levels sufficient for phenotypic analysis in 20/20 clinical isolates. EC(50) values for the NS3 inhibitor BILN-2061 ranged from 0.2 to 1.1nM for 20 genotype 1 patient isolates. Significantly reduced susceptibility to BILN-2061 was observed with mutant/wild type mixtures of 5%/95% for the D168V or 50%/50% for A156T resistance mutations in the NS3. These shuttle vectors can be used to evaluate candidate drugs and assist in the development of new drugs targeting the NS3 protease.

Low-level K65R mutation in HIV-1 reverse transcriptase of treatment-experienced patients exposed to abacavir or didanosine.

BACKGROUND: Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF). METHODS: An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%. RESULTS: Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response. CONCLUSIONS: Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant.

Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz.

The presence of drug-associated mutations among ART-naive, HIV-1(+) patients may compromise the response to antiviral therapy. We evaluated the effect of preexisting drug-associated resistance mutations to the response in treatment-naive patients to therapy with emtricitabine (FTC) or stavudine (d4T) in combination with didanosine (ddI) and efavirenz (EFV). Study FTC-301A compared emtricitabine once daily (QD) with stavudine twice daily in combination with didanosine and efavirenz in ART-naive patients. Genotypic analysis was performed on baseline plasma HIV-1 RNA for all available samples and at time of virologic failure (VF). Drug resistance mutations present at baseline were evaluated as predictors of VF using logistic regression. VF rates were compared between subgroups using a two-sided exact test. Baseline drug resistance mutations were observed in 90/546 (16.5%) patients: 56/90 (62.2%) with nonnucleoside analogue (NNRTI) mutations and 42/90 (46.6%) with nucleoside analogue mutations. In a stepwise, multiple regression analysis, the presence of the K103N mutation at initiation of therapy was associated with VF in both arms (p = 0.001), however, there was a higher incidence of VF in the stavudine arm compared to the emtricitabine arm regardless of the presence or absence of mutations at baseline (p = 0.001). In this study, the presence of drug-associated resistance mutations in ART-naive patients was significantly correlated with subsequent development of virologic failure underscoring the utility of testing for resistance in addition to the use of potent and well-tolerated first line regimens in treatment-naive patients.

MultiCode-RTx real-time PCR system for detection of subpopulations of K65R human immunodeficiency virus type 1 reverse transcriptase mutant viruses in clinical samples.

We report a real-time PCR assay capable of detecting drug-resistant human immunodeficiency virus type 1 reverse transcriptase K65R mutant virus at a level of 0.5% in polymorphic patient plasma specimens. Fifty-three treatment-naïve and 20 treatment-experienced specimens were successfully genotyped with the new method. Results were in agreement with population sequencing and the labor-intensive single-genome sequencing method.