Timing of Antibiotics in Septic Patients With Septic Arthritis

Septic arthritis (SA) is an uncommon and devastating infectious inflammatory disease of the synovial joint. SA has an incidence of approximately 2 to 6 infections per 100,000 persons.¹ Comorbidities that increase the risk of developing SA include sickle cell anemia, hemophilia, HIV, Neisseria, diabetes, rheumatoid or osteoarthritis, immunocompromised states, intravenous drug use, prosthetic joints, and/or joint surgery.² The hip is the most commonly affected joint in the pediatric population, while the knee is the most commonly affected joint in the adult population.³ Although the word “septic” in septic arthritis means an infection of the joint, it does not mean that the patient is actually septic.
  
While the terminology and diagnostic criteria for sepsis differ across organizations and has evolved over the years, sepsis was defined in 2016 by the Third International Consensus Definitions for Sepsis and Septic Shock as the dysregulated host response to infection⁴ that causes a systemic inflammatory response syndrome and/or organ dysfunction operationalized by an increase in the Sequential Organ Failure Assessment score of 2 or more points.⁵ If left untreated, SA can have dangerous sequelae such as sepsis and septic shock. Septic shock is a major cause of ICU mortality⁶; therefore, guidelines have been adopted to standardize care for patients with septic shock and improve survival outcomes. Current recommendations include timely administration of 30-mL/kg volume resuscitation, blood cultures, early source control, and initiation of empiric antibiotic therapy within one hour of sepsis recognition.^5,7
 
Given the abundance of data regarding the need for early antibiotic therapy in sepsis, antibiotic therapy is typically started before synovial fluid aspirate (SFA) has been collected in patients with suspected SA. Little is known about the effects of initiating antibiotic therapy prior to SFA on the diagnostic yield of SFA analysis. The bigger question remains: Should ICU clinicians initiate or delay antibiotics in patients with sepsis when SFA analysis could take several hours? In this Concise Critical Appraisal, we review a recent article by Puzzitiello et al, who explored the effect of antibiotic administration on SFA analysis.⁸
 
The authors performed a monocentric, retrospective review of patients with native joint SA at Tufts Medical Center. Using International Classification of Diseases (ICD), Ninth Revision and Tenth Revision codes for SA, 614 patients were identified from hospital medical records. Patients were excluded if they did not meet the specified criteria for native joint SA: 1) a pathogen was isolated from the synovial fluid; 2) a pathogen was isolated from a source other than synovial fluid, and the clinical presentation was typical of SA; or 3) the synovial fluid was turbid, the clinical presentation was typical of SA, and crystals were absent. Other exclusion criteria included age younger than 18 years, prior replacement of the affected joint, no aspiration performed, inability to determine timing of antibiotic administration, or history of SA in the same joint within the prior 30 days. Patients with sepsis were not excluded.
 
Of the 126 patients included, 63.5% received antibiotics prior to joint aspiration. These patients with preaspiration antibiotics were subsequently found to have significantly fewer white blood cells (WBCs) in the synovial fluid compared to those without preaspiration antibiotics (51,379.1/mm³ vs. 92,162.7/mm³; P < .001). Patients with preaspiration antibiotics also had a lower percentage of polymorphonuclear neutrophils (83.6% vs. 91.9%; P = .01) and decreased rates of culture positivity (32.5% vs. 59.1%, P = .008). The authors reported that patients with synovial fluid WBC counts of less than 50,000/mm³ experienced a significant delay in the time from joint aspiration to operative intervention (10.5 hours vs. 17.9 hours, P = .02). These results may pose a challenge for clinicians using the historical WBC count diagnostic threshold for SA of 50,000/mm³.
 
The Puzzitiello article sheds light on an important dilemma for critical care clinicians: In a patient with sepsis from SA, should antibiotics be delayed until after arthrocentesis? If so, how long should antibiotics be delayed? According to the data collected by the authors, antibiotics should likely be delayed in patients who lack evidence of sepsis and are clinically stable. Antibiotics can also be delayed if an SFA analysis can occur within 1 hour of sepsis recognition. However, in patients with sepsis where SFA analysis can take several hours, early initiation of antibiotics still supersedes the need to optimize diagnostic accuracy of arthrocentesis. Although preaspiration antibiotic treatment can skew the results of diagnostic arthrocentesis and lead to delays in operative treatment in SA, there is an abundance of data regarding the effects of delaying antibiotics on morbidity and mortality in septic patients.⁶
 
The article has several limitations, including the small sample size, the monocentric and retrospective design, and the reliance on electronic medical records for approximating the timing of antibiotic therapy. Further data are needed to specifically evaluate the effect antibiotic timing in septic patients with SA. Moreover, the data collected by Puzzitiello et al emphasize the need for having clinicians capable of obtaining SFA analysis within a short time period when patients are septic from SA.

 
References

1. Hassan AS, Rao A, Manadan AM, Block JA. Peripheral bacterial septic arthritis: review of diagnosis and management. J Clin Rheumatol. 2017 Dec;23(8):435-442.
2. Horowitz DL, Katzap E, Horowitz S, Barilla-LaBarca ML. Approach to septic arthritis. Am Fam Physician. 2011 Sep 15;84(6):653-660.
3. Visser S, Tupper J. Septic until proven otherwise: approach to and treatment of the septic joint in adult patients. Can Fam Physician. 2009 Apr;55(4):374-375.
4. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-810.
5. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.
6. Prest J, Nguyen T, Rajah T, Prest AB, Sathananthan M, Jeganathan N. Sepsis-related mortality rates and trends based on site of infection. Crit Care Explor. 2022 Oct 10;4(10):e0775.
7. Kumar A, Zarychanski R, Light B, et al; Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med. 2010 Sep;38(9):1773-1785.
8. Puzzitiello RN, Lipson SE, Michaud RG Jr, et al. Effect of antibiotic administration before joint aspiration on synovial fluid white blood cell count in native joint septic arthritis. Open Forum Infect Dis. 2024 Jan 11;11(1):ofad600.