Citations

Cefiderocol (formerly S-649266) is a novel siderophore-conjugated cephalosporin with activity against a broad array of multidrug-resistant (MDR), aerobic Gram-negative bacilli. The siderophore component binds iron and uses active iron transport for drug entry into the bacterial periplasmic space. The cephalosporin moiety is the active antimicrobial component, structurally resembling a hybrid between ceftazidime and cefepime. Like other β-lactam agents, the principal bactericidal activity of cefiderocol occurs via inhibition of bacterial cell wall synthesis by binding of penicillin-binding proteins (PBPs) and inhibiting peptidoglycan synthesis, leading to cell death.

Abstract Background Owing to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection. In the current study, we evaluated rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis. Methods Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a Kirschner wire (K-wire) implanted in each. After 4 weeks of infection, rifampin, rifabutin, or rifapentine were administered, alone or with vancomycin. Tibiae and K-wires were cultured, and medians were reported as log10 colony-forming units (CFUs) per gram of bone or log10 CFUs per K-wire, respectively. Results Rifampin, rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02, and 0.10 log10 CFUs/g, respectively) than did no treatment (4.36 log10 CFUs/g) or vancomycin alone (4.64 log10 CFUs/g) (both P ≤ .02). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 CFUs/g per K-wire, respectively. In contrast, rifampin, rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 CFUs per K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group. Conclusions Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal periprosthetic joint infections.

Abstract IDSA Disclaimer As of the time of this publication, updates have been made to IDSA’s Guidelines on the Diagnosis of COVID-19. For the most updated version of these guidelines, please go to https://www.idsociety.org/covid19guidelines. Background Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19). Direct detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids in respiratory tract specimens informs patient, healthcare institution, and public health–level decision-making. The number of available SARS-CoV-2 nucleic acid detection tests is rapidly increasing, as is the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) recognized a significant need for frequently updated systematic reviews of the literature to inform evidence-based best practice guidance. Objective The IDSA’s goal was to develop an evidence-based diagnostic guidelines to assist clinicians, clinical laboratorians, patients, and policy makers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, the society provides a conceptual framework for understanding molecular diagnostic test performance, discusses the nuance of test result interpretation in a variety of practice settings, and highlights important unmet research needs in the COVID-19 diagnostic testing arena. Methods IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of evidence and make testing recommendations. Results The panel agreed on 15 diagnostic recommendations. Conclusions Universal access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention, and the public response to the COVID-19 pandemic. Information on the clinical performance of available tests is rapidly emerging, but the quality of evidence of the current literature is considered low to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is recommended for asymptomatic individuals who have had a known or suspected contact with a COVID-19 case. Testing asymptomatic individuals without known exposure is suggested when the results will impact isolation/quarantine/personal protective equipment usage decisions, dictate eligibility for surgery, or inform administration of immunosuppressive therapy. Ultimately, prioritization of testing will depend on institution-specific resources and the needs of different patient populations.

AbstractThere is interest in novel synovial fluid biomarkers for the detection of periprosthetic joint infection (PJI). Here, we assessed the diagnostic accuracy of 23 simple or sophisticated synovial fluid biomarkers for periprosthetic hip or knee infection detection. One hundred seven subjects were studied, 57 of whom had aseptic failure (AF) and 50 PJI. The following synovial fluid biomarkers were tested using spectrophotometric assays, immunoassays, lateral flow tests, or test strips: leukocyte count, monocyte percentage, lymphocyte percentage, neutrophil percentage, C‐reactive protein (CRP), glucose, lactate, granulocyte‐macrophage colony‐stimulating factor, interferon‐γ, interleukin‐1β (IL‐1β), IL‐2, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, IL‐17A, IL‐23, tumor necrosis factor‐α, α‐defensin, and leukocyte esterase. The best‐performing synovial fluid biomarkers to differentiate PJI from AF—that is, those with highest area under the curve compared to all other biomarkers—were leukocyte count, percent neutrophils and percent monocytes, CRP, and α‐defensin (P < .0001).

Abstract 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.

Abstract Background Rapid blood culture diagnostics are of unclear benefit for patients with gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, randomized, controlled trial comparing outcomes of patients with GNB BSIs who had blood culture testing with standard-of-care (SOC) culture and antimicrobial susceptibility testing (AST) vs rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno System (RAPID). Methods Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship (AS) review or RAPID with AS. The primary outcome was time to first antibiotic modification within 72 hours of randomization. Results Of 500 randomized patients, 448 were included (226 SOC, 222 RAPID). Mean (standard deviation) time to results was faster for RAPID than SOC for organism ID (2.7 [1.2] vs 11.7 [10.5] hours; P &lt; .001) and AST (13.5 [56] vs 44.9 [12.1] hours; P &lt; .001). Median (interquartile range [IQR]) time to first antibiotic modification was faster in the RAPID arm vs the SOC arm for overall antibiotics (8.6 [2.6–27.6] vs 14.9 [3.3–41.1] hours; P = .02) and gram-negative antibiotics (17.3 [4.9–72] vs 42.1 [10.1–72] hours; P &lt; .001). Median (IQR) time to antibiotic escalation was faster in the RAPID arm vs the SOC arm for antimicrobial-resistant BSIs (18.4 [5.8–72] vs 61.7 [30.4–72] hours; P = .01). There were no differences between the arms in patient outcomes. Conclusions Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for gram-negative BSIs. Clinical Trials Registration NCT03218397.

Whole-genome sequencing (WGS) is now routinely performed in clinical microbiology laboratories to assess isolate relatedness. With appropriately developed analytics, the same data can be used for prediction of antimicrobial susceptibility. We assessed WGS data for identification using open-source tools and antibiotic susceptibility testing (AST) prediction using ARESdb compared to matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification and broth microdilution phenotypic susceptibility testing on clinical isolates from a multicenter clinical trial of the FDA-cleared Unyvero lower respiratory tract infection (LRTI) application (Curetis).

Mini We compared the sensitivity and specificity of peri-implant tissue culture to the vortexing–sonication technique for the diagnosis of spinal implant infection (SII). Lower thresholds of sonicate fluid culture positivity showed increased sensitivity with maintained specificity. We recommend a threshold of 20 CFU/10 mL for sonicate culture positivity for the diagnosis of SII. Study Design. This is a retrospective study comparing the diagnosis of spinal implant infection (SII) by peri-implant tissue culture to vortexing–sonication of retrieved spinal implants. Objective. We hypothesized that vortexing–sonication would be more sensitive than peri-implant tissue culture. Summary of Background Data. We previously showed implant vortexing–sonication followed by culture to be more sensitive than standard peri-implant tissue culture for diagnosing of SII. In this follow-up study, we analyzed the largest sample size available in the literature to compare these two culture methods and evaluated thresholds for positivity for sonicate fluid for SII diagnosis. Methods. We compared peri-implant tissue culture to the vortexing–sonication technique which samples bacterial biofilm on the surface of retrieved spinal implants. We evaluated different thresholds for sonicate fluid positivity and assessed the sensitivity and specificity of the two culture methods for the diagnosis of SII. Results. A total of 152 patients were studied. With more than 100 colony forming units (CFU)/10 mL as a threshold for sonicate fluid culture positivity, there were 46 patients with SII. The sensitivities of peri-implant tissue and sonicate fluid culture were 65.2% and 79.6%; the specificities were 88.7% and 93.4%, respectively. With more than 50 CFU/10 mL as a threshold, there were 50 patients with SII. The sensitivities of peri-implant tissue and sonicate fluid culture were 68.0% and 76.0%; the specificities were 92.2% for both methods. Finally, with more than or equal to 20 CFU/10 mL as a threshold, there were 52 patients with SII. The sensitivities of peri-implant tissue and sonicate fluid culture were 69.2% and 82.7%; the specificities were 94.0% and 92.0%, respectively. Conclusion. Implant sonication followed by culture is a sensitive and specific method for the diagnosis of SII. Lower thresholds for defining sonicate fluid culture positivity allow for increased sensitivity with a minimal decrease in specificity, enhancing the clinical utility of implant sonication. Level of Evidence: 4

Abstract Aims Wound infections involving Candida albicans can be challenging to treat because of the fungus’ ability to penetrate wound tissue and form biofilms. The goal of this study was to assess the activity of a hypochlorous acid (HOCl)-generating electrochemical scaffold (e-scaffold) against C. albicans biofilms in vitro and on porcine dermal explants (ex vivo). Methods and Results C. albicans biofilms were grown either on acrylic-bottom six-well plates (in vitro) or on skin tissue excised from porcine ears (ex vivo), and the polarized e-scaffold was used to generate a continuous supply of low concentration HOCl near biofilm surfaces. C. albicans biofilms grown in vitro were reduced to undetectable amounts within 24 h of e-scaffold exposure, unlike control biofilms (5·28 ± 0·034 log10 (CFU cm-2); P &lt; 0·0001). C. albicans biofilms grown on porcine dermal explants were also reduced to undetectable amounts in 24 h, unlike control explant biofilms (4·29 ± 0·057 log10 (CFU cm-2); P &lt; 0·0001). There was a decrease in the number of viable mammalian cells (35·6 ± 6·4%) in uninfected porcine dermal explants exposed to continuous HOCl-generating e-scaffolds for 24 h compared to explants exposed to nonpolarized e-scaffolds (not generating HOCl) (P &lt; 0·05). Conclusions Our HOCl-generating e-scaffold is a potential antifungal-free strategy to treat C. albicans biofilms in chronic wounds. Significance and Impact of the Study Wound infections caused by C. albicans are difficult to treat due to presence of biofilms in wound beds. Our HOCl producing e-scaffold provides a promising novel approach to treat wound infections caused by C. albicans.