Department of Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Clin Orthop Relat Res. 2022 Aug 1;480(8):1463-1473. doi: 10.1097/CORR.0000000000002186. Epub 2022 Apr 5.
A consensus definition recently was formulated for fracture-related infection, which centered on confirmatory criteria including conventional cultures that take time to finalize and have a 10% to 20% false-negative rate. During this time, patients are often on broad-spectrum antibiotics and may remain hospitalized until cultures are finalized to adjust antibiotic regimens.
QUESTIONS/PURPOSES: (1) What is the diagnostic accuracy of isothermal microcalorimetry, and how does its accuracy compare with that of conventional cultures? (2) Does isothermal microcalorimetry decrease time to detection (or diagnosis) of fracture-related infection compared with conventional cultures? (3) Does isothermal microcalorimetry have a diagnostic accuracy or time advantage over conventional cultures in patients on chronic suppressive antibiotics?
Between July 2020 and August 2021, we treated 310 patients with concerns for infection after prior fracture repair surgery. Of those, we considered all patients older than 18 years of age with fixation hardware in place at the time of presentation as potentially eligible. All included patients returned to the operating room with cultures obtained and assessed by both isothermal microcalorimetry and conventional cultures, and all were diagnosed using the consensus criteria for fracture-related infection. Based on that, 81% (250 of 310) of patients were eligible; a further 51% (157 of 310) were excluded because of the following reasons: the capacity of the isothermal microcalorimetry instrument limited the throughput on that day (34% [106 of 310]), they had only swab cultures obtained in surgery (15% [46 of 310]), or they had less than 3 months follow-up after surgery for infectious concerns (2% [5 of 310]), leaving 30% (93 of 310) of the originally identified patients for analysis. We obtained two to five cultures from each patient during surgery, which were sent to our clinical microbiology laboratory for standard processing (conventional cultures). This included homogenization of each tissue sample individually and culturing for aerobic, anaerobic, acid-fast bacilli, and fungal culturing. The remaining homogenate from each sample was then taken to our orthopaedic research laboratory, resuspended in growth media, and analyzed by isothermal microcalorimetry for a minimum of 24 hours. Aerobic and anaerobic cultures were maintained for 5 days and 14 days, respectively. Overall, there were 93 patients (59 males), with a mean age of 43 ± 14 years and a mean BMI of 28 ± 8 kg/m 2 , and 305 tissue samples (mean 3 ± 1 samples per patient) were obtained and assessed by conventional culturing and isothermal microcalorimetry. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of isothermal microcalorimetry to diagnose fracture-related infection were compared with conventional cultures using a McNemar test based on the consensus definition of fracture-related infection. This consensus criteria is comprised of two levels of certainty for the diagnostic variables. The first is confirmatory criteria, where infection is considered definitely present and includes the presence of fistula/sinus tract/wound breakdown, purulent drainage or the presence of pus, presence of microorganisms in deep tissue specimens on histopathologic examination, presence of more than five neutrophils/high-powered field by histopathologic examination (only for chronic/late onset cases), and identification of phenotypically indistinguishable pathogens by conventional culture from at least two separate deep tissue/implant specimens. The second is suggestive criteria in which further investigation is required to achieve confirmatory status. Fracture-related infection was diagnosed for this study to minimize subjectivity based on the presence of at least one of the confirmatory criteria as documented by the managing surgeon. When suggestive criteria were present without confirmatory criteria, patients were considered negative for fracture-related infection and followed further in clinic after surgical exploration (n = 25 patients). All 25 patients deemed not to have fracture-related infection were considered infection-free at latest follow-up (range 3 to 12 months). The time to detection or diagnosis was recorded and compared via the Mann-Whitney U test.
Using the consensus criteria for fracture-related infection, there were no differences with the numbers available between isothermal microcalorimetry and conventional cultures in terms of sensitivity (87% [95% confidence interval 77% to 94%] versus 81% [95% CI 69% to 89%]), specificity (100% [95% CI 87% to 100%] versus 96% [95% CI 79% to 99%]), PPV (100% [95% CI 90% to 100%] versus 98% [95% CI 89% to 99%]), NPV (74% [95% CI 60% to 84%] versus 65% [95% CI 52% to 75%]), or accuracy (90% [95% CI 83% to 96%] versus 85% [95% CI 76% to 91%]; p = 0.13). The concordance by sample between conventional cultures and isothermal microcalorimetry was 85%. Isothermal microcalorimetry had a shorter median (range) time to detection or diagnosis compared with conventional cultures (2 hours [0.5 to 66] versus 51 hours [18 to 147], difference of medians 49 hours; p < 0.001). Additionally, 32 patients used antibiotics for a median (range) duration of 28 days (7 to 1095) before presentation. In these unique patients, there were no differences with the numbers available between isothermal microcalorimetry and conventional cultures in terms of sensitivity (89% [95% CI 71% to 98%] versus 74% [95% CI 53% to 88%]), specificity (100% [95% CI 48% to 100%] versus 83% [95% CI 36% to 99%]), PPV (100% [95% CI 85% to 100%] versus 95% [95% CI 77% to 99%]), NPV (63% [95% CI 37% to 83%] versus 42% [95% CI 26% to 60%]), or accuracy (91% [95% CI 75% to 98%] versus 78% [95% CI 57% to 89%]; p = 0.17). Isothermal microcalorimetry again had a shorter median (range) time to detection or diagnosis compared with conventional cultures (1.5 hours [0.5 to 48] versus 51.5 hours [18 to 125], difference of medians 50 hours; p < 0.001).
Given that isothermal microcalorimetry considerably decreases the time to the diagnosis of a fracture-related infection without compromising the accuracy of the diagnosis, managing teams may eventually use isothermal microcalorimetry-pending developmental improvements and regulatory approval-to rapidly detect infection and begin antibiotic management while awaiting speciation and susceptibility testing to modify the antibiotic regimen. Given the unique thermograms generated, further studies are already underway focusing on speciation based on heat curves alone. Additionally, increased study sizes are necessary for both overall fracture-related infection diagnostic accuracy and test performance on patients using long-term antibiotics given the promising results with regard to time to detection for this groups as well.
Level II, diagnostic study.
最近提出了一种骨折相关感染的共识定义，该定义集中在确认标准上，包括需要时间来完成且假阴性率为 10%至 20%的常规培养。在此期间，患者通常接受广谱抗生素治疗，并且可能在培养结果出来之前一直住院，以调整抗生素方案。
问题/目的：（1）等温微热量计的诊断准确性如何，其准确性与常规培养相比如何？（2）与常规培养相比，等温微热量计是否能缩短骨折相关感染的检测（或诊断）时间？（3）等温微热量计在使用慢性抑制性抗生素的患者中，与常规培养相比，在诊断准确性或时间上是否具有优势？
在 2020 年 7 月至 2021 年 8 月期间，我们治疗了 310 例先前骨折修复手术后出现感染的患者。其中，我们考虑了所有在就诊时固定硬件在位的年龄大于 18 岁的患者，这些患者可能有资格接受检查。所有纳入的患者都返回手术室进行培养，通过等温微热量计和常规培养进行评估，并且所有患者均根据骨折相关感染的共识标准进行诊断。基于此，81%（250/310）的患者符合条件；另外 51%（157/310）的患者由于以下原因被排除在外：等温微热量计仪器的容量限制了当天的吞吐量（34%[310/106]），他们只在手术中获得了拭子培养（15%[310/46]），或者他们在手术后的 3 个月内出现了感染的顾虑（2%[310/5]），只有 30%（93/310）的最初确定的患者接受了分析。我们从每位患者的手术中获得了 2 到 5 个培养物，这些培养物被送到我们的临床微生物学实验室进行标准处理（常规培养）。这包括将每个组织样本单独均质化，并进行需氧、厌氧、抗酸杆菌和真菌培养。从每个样本中剩余的匀浆被重新悬浮在生长培养基中，并通过等温微热量计进行至少 24 小时的分析。需氧和厌氧培养分别持续 5 天和 14 天。总的来说，有 93 名患者（59 名男性），平均年龄为 43 ± 14 岁，平均 BMI 为 28 ± 8 kg/m 2 ，共获得和评估了 305 个组织样本（平均每个患者 3 ± 1 个样本），通过常规培养和等温微热量计进行了评估。使用基于骨折相关感染共识定义的 McNemar 检验比较了等温微热量计诊断骨折相关感染的敏感性、特异性、阳性预测值（PPV）、阴性预测值（NPV）和准确性。该共识标准由两个级别的诊断变量确定。第一个是确认标准，其中感染被认为是明确存在的，包括瘘管/窦道/伤口破裂、脓性引流或脓液、组织病理学检查中深部组织标本存在微生物、组织病理学检查中每高倍镜视野（HPF）中性粒细胞数超过 5 个（仅用于慢性/迟发性病例）以及至少从两个不同的深部组织/植入物标本中常规培养鉴定出表型无法区分的病原体。第二个是提示标准，需要进一步调查以达到确认状态。本研究为了尽量减少基于主治医生记录的确认标准的主观性，将骨折相关感染的诊断定为阴性（n=25 名患者）。在没有确认标准的情况下，患者被认为没有骨折相关感染，并在手术探查后进一步在诊所随访（n=25 名患者）。所有被认为没有骨折相关感染的 25 名患者在最新随访时（3 至 12 个月）均无感染。记录并比较了检测或诊断的时间，通过 Mann-Whitney U 检验进行比较。
使用骨折相关感染的共识标准，等温微热量计和常规培养在敏感性（87%[95%置信区间 77%至 94%]与 81%[95%置信区间 69%至 89%]）、特异性（100%[95%置信区间 87%至 100%]与 96%[95%置信区间 79%至 99%]）、PPV（100%[95%置信区间 90%至 100%]与 98%[95%置信区间 89%至 99%]）、NPV（74%[95%置信区间 60%至 84%]与 65%[95%置信区间 52%至 75%]）或准确性（90%[95%置信区间 83%至 96%]与 85%[95%置信区间 76%至 91%]）方面没有差异（p=0.13）。常规培养和等温微热量计之间的样本一致性为 85%。等温微热量计的检测或诊断中位（范围）时间明显短于常规培养（2 小时[0.5 至 66]与 51 小时[18 至 147]，中位数相差 49 小时；p<0.001）。此外，32 名患者在就诊前使用抗生素的中位（范围）时间为 28 天（7 至 1095）。在这些特殊患者中，等温微热量计和常规培养在敏感性（89%[95%置信区间 71%至 98%]与 74%[95%置信区间 53%至 88%]）、特异性（100%[95%置信区间 48%至 100%]与 83%[95%置信区间 36%至 99%]）、PPV（100%[95%置信区间 85%至 100%]与 95%[95%置信区间 77%至 99%]）、NPV（63%[95%置信区间 37%至 83%]与 42%[95%置信区间 26%至 60%]）或准确性（91%[95%置信区间 75%至 98%]与 78%[95%置信区间 57%至 89%]）方面没有差异（p=0.17）。等温微热量计的检测或诊断中位（范围）时间也明显短于常规培养（1.5 小时[0.5 至 48]与 51.5 小时[18 至 125]，中位数相差 50 小时；p<0.001）。
鉴于等温微热量计在不影响诊断准确性的情况下大大缩短了骨折相关感染的诊断时间，管理团队最终可能会使用等温微热量计（等待发展改进和监管批准）来快速检测感染，并开始抗生素管理，同时等待特异性和药敏试验来修改抗生素方案。鉴于生成的独特热图，已经有进一步的研究侧重于基于热曲线的特异性，而不是基于培养的特异性。此外，还需要进行更大规模的研究，以确定整体骨折相关感染的诊断准确性和患者使用长期抗生素时的检测性能，因为这些研究在这些组中也有很好的检测时间结果。
二级，诊断研究。
