Clinical Guidelines for the Antimicrobial Treatment of Bone and Joint Infections in Korea
Associated Data
Abstract
There are many various diseases in the bone and joint infections, and we tried to make antimicrobial treatment guidelines for common infectious diseases based on available data for microbiology and clinical trials. This guidelines focused on the treatment of osteomyelitis and septic arthritis, which can be experienced by physicians at diverse clinical settings. This guidelines is not applicable to diabetic foot infections, postoperative infections or post-traumatic infections which need special considerations. The guidelines for those conditions will be separately developed later. Surgical treatment of bone and joint infections, pediatric bone and joint infection, tuberculous bone and joint infection, and prophylactic antibiotic use were not included in this guideline.
Introduction
1. Background and purpose
In recent years, the clinical practice of treating bone and joint infection has changed. Despite new therapeutic modalities being developed, physicians still consider bone and joint infections difficult to cure due to the high rate of treatment failure and recurrence. Osteomyelitis and septic arthritis usually refer to infections of the upper and lower extremities of bones, spinal bone structures, and joints. These guidelines recommend antimicrobial therapy for the treatment of osteomyelitis and septic arthritis for primary physicians, trainees of teaching hospitals, medical specialists, orthopedic surgery specialists, and neurosurgery specialists.
2. Scope
These guidelines suggest antimicrobial therapy for the treatment of osteomyelitis and septic arthritis based on evidence acquired from the domestic and foreign literature. We will develop differentially further medical guidelines on the diagnosis of osteomyelitis and septic arthritis, diabetic foot infection, surgical site infection including arthroplasty, and post-trauma infection.
The surgical treatment of osteomyelitis and arthritis, pediatric osteomyelitis and arthritis, and tubercular osteomyelitis and arthritis, and the prophylactic use of preoperative antibiotics, are excluded from these guidelines.
3. Guideline development methods
1) Establish a committee for developing the guidelines
Through multidisciplinary cooperation, the committee was composed of 12 people, including infectious disease specialists, orthopedic surgery specialists, and preventive medicine specialists.
2) Define the scope of the guidelines
The guideline development committee created these criteria based on the five considerations of PIPOH (Population, Intervention, Professionals, Outcomes, Healthcare setting). We defined the scope of the guidelines in a committee that discussed the state of the disease in a population, therapeutic interventions, target professionals, patient outcomes (focused on increasing survival rate or improving quality of life), and the customization of individual healthcare settings.
3) Framing key questions
Defining key questions was the first stage; it involved collecting evidence and data and conducting evaluations. After reviewing domestic and foreign medical guidelines and literature, the committee identified the development of these guidelines as the key question.
4) Searching for evidence
We searched the PubMed (www.pubmed.gov) and KoreaMed (www.koreamed.org) databases for articles and guidelines published between January 1975 and December 2012 using the keywords "Arthritis, Infectious" [MeSH] or "septic arthritis" and "guideline" or "systematic". The committee assessed studies for potential eligibility and selected articles from the literature.
5) Writing the guidelines and clarifying the strength of the recommendations
The guideline development committee drafted the guidelines and classified the evidence according to three criteria (I, II, III) after reviewing the literature based on each key question. We classified evidence as A, B, or C when determining the strength of a recommendation. Our development committee applied the strength of the recommendation and the quality of evidence for the recommendation according to information from the Infectious Diseases Society of America (Table 1).
Table 1
Strength of recommendation and quality of evidence for recommendation
6) External specialists review and approval
The guidelines were presented to the Korean Society for Chemotherapy on April 14, 2012. Specialist groups and society members provided feedback freely. Based on their opinions, we revised and finalized our guidelines.
Practice guidelines
1. Osteomyelitis
1) Epidemiology and classification
Osteomyelitis is defined as inflammatory changes of bone tissue and accompanying bone destruction due to pyogenic organisms [1]. Once symptoms appear and as time progresses, the disease can be classified as acute, subacute, or chronic. However, osteomyelitis is a complicated condition as it is influenced by not only the time of disease onset, but also pathogenesis, affected site, and local blood supply. Thus, classification methods were used when considering these points.
Waldvogel's classification was originally presented in 1970, dividing osteomyelitis into hematogenous, contiguous, and chronic osteomyelitis categories according to pathogenesis and the time of disease onset (Table 2). Contiguous osteomyelitis was classified according to the presence or absence of systemic vascular disease. Waldvogel's classification system was organized according to pathogenesis; thus, it is helpful to make assumptions about infecting pathogens and choose the appropriate empirical antibiotic treatment [2]. Hematogenous osteomyelitis accounts for approximately 20% of all osteomyelitis cases; it usually develops in children. In cases of osteomyelitis related to parenteral drug abuse, the spine is commonly involved [3]. The number of hematogenous osteomyelitis cases has been decreasing thanks to social and economic changes as well as the advancement of medical technology, whereas the number of contiguous osteomyelitis cases has been rising because of increased numbers of traffic accidents and an increased number of arthroplasty operations. Contiguous osteomyelitis accounts for 80% of all osteomyelitis cases. It develops in soft tissues or secondary to surgery or trauma, and occurs more often in adults than in children. It is commonly associated with vascular insufficiency of the infected area or prosthesis. In such cases, it is hard to be cured.
Cierny-Mader's classification system does not categorize the disease according to its duration (i.e., acute or chronic). Rather, it classifies the disease based on the anatomical extent of necrosis of the infected bone sites, the patient's physiological state and the systemic or local impact of disease on function (Table 3, Fig. 1) [4]. Cierny-Mader's classification system is frequently used in clinical practice because it is especially helpful for determining treatment and prognosis in patients with long bone osteomyelitis. It is useful as a tool for determining whether surgery is appropriate, and for selecting surgical methods.
Osteomyelitis Type I indicates that the infection is limited to the medulla; it includes primary hematogenous infections. Osteomyelitis Type II mostly occurs through a direct inoculation or a contiguous focus of infection. Osteomyelitis Type III usually involves cortical bone. Although the stability of the bone is maintained, necrotic areas need to be removed. Osteomyelitis Type IV indicates that all layers of bone are infected and that all necrotic bone should be removed. Therefore, the structural stability of the bone is compromised. However, it is important to note that the osteomyelitis categories of the Cierny-Mader's classification system can change dynamically according to the patient's condition, administration of antibiotic therapy, and other treatments. In addition, this classification system would not be applicable to osteomyelitis in special situations, such as peri-prosthetic osteomyelitis and vertebral osteomyelitis.
2) Distribution of causative pathogens
Isolation of the causative pathogen in osteomyelitis is very important for determining the diagnosis and selecting effective treatments. Data from other countries indicate that Staphylococcus aureus is the most common causative pathogen in most types of osteomyelitis. Enterobacteriaceae, coagulase-negative staphylococci (CoNS), and streptococci (bite wounds, bedsores, and diabetic foot infections) are also common causative pathogens [1, 5, 6]. Pseudomonas aeruginosa is a common causative pathogen when the disease is acquired in hospitals. The number of tuberculous osteomyelitis patients has recently been growing in parallel with an increasing number of AIDS patients, while fungal infection cases remain rare.
According to a domestic article dealing exclusively with spondylitis, causative pathogens were isolated in 71 of 101 cases; the results indicated that S. aureus was the most common pathogen, accounting for 36.6% of isolates. Meanwhile, 19.2% of S. aureus isolates were methicillin-resistant S. aureus (MRSA). Viridans-group streptococci, Streptococcus agalactiae, and Streptococcus pneumoniae accounted for 18.3%, 8.5%, and 4.2% of isolates, respectively. Gram-negative pathogens accounted for 18.3% of isolates, and included Escherichia coli (9.9%) and P. aeruginosa (4.2%) [7]. Other domestic data indicated that S. aureus accounted for the largest proportion (39.8%) at 37 cases among 93 cases of vertebral osteomyelitis; 37.8% of which was MRSA. Meanwhile, S. epidermidis accounted for 12.9% of isolates, and streptococci accounted for 16.1%. Gram-negative pathogens accounted for 24.7% of all vertebral osteomyelitis cases. E. coli was the most common (12.9%), followed by Klebsiella pneumoniae (3.2%) and P. aeruginosa (2.2%). No significant differences were detected among the studies [8].
The distribution of causative pathogen in bacterial osteomyelitis differs according to patient age, route of disease dispersion, clinical situation, and the severity of clinical manifestation [6, 9]. Considering age, 90% of hematogenous osteomyelitis occurring in healthy children develops as a result of S. aureus infection. Hematogenous osteomyelitis due to Haemophilus influenzae is also common in children who have not received H. influenzae type B vaccination (Table 4) [2, 5, 6]. S. aureus, S. epidermidis, P. aeruginosa, Serratia marcescens, and E. coli are the common causative pathogens in adults with osteomyelitis.
Hematogenous osteomyelitis mainly occurs as a result of one pathogen, but contiguous osteomyelitis can occur through infection with a single pathogen or multiple pathogens [5]. Patients with vascular insufficiency frequently develop mixed infection with S. aureus, CoNS, Enterobacteriaceae, streptococci, enterococci, and anaerobic pathogens. In patients with osteomyelitis related to prosthesis, the causative pathogen is most commonly S. aureus. In such patients, we should consider the possibility of infection by S. epidermidis, P. aeruginosa, and Propionibacterium spp. (Table 5) [1, 5].
On the other hand, we also have to consider the possibility of infection with Brucella spp., Coxiella burnetii (Q fever), and fungal infection, depending on the patient's immunity, occupation, and traveling history. If patients have risk factors for candida infection, such as a history of treatment with broad-spectrum antibiotics, use of central catheters, and repeated isolation of Candida spp. in the absence of another pathogen, we must suspect Candida osteomyelitis.
3) Clinical findings
Hematogenous osteomyelitis is frequently seen in children, while contiguous osteomyelitis occurs in adults. Patients with acute osteomyelitis, especially hematogenous osteomyelitis, present localized pain of several days. In young children, systemic symptoms in particular, such as fever, irritability, and lethargy, are accompanied by local symptoms such as tenderness, local heating, and swelling [1]. However, in the case of vertebral, hip joint, and pelvic osteomyelitis, specific symptoms and signs may be absent, except pain. In addition, acute osteomyelitis commonly occurs on the metaphysis in children and the diaphysis in adults. Occasionally, the disease spreads to nearby joints and progresses to septic arthritis. In most cases, the infected bones are tender, and the range of motion around the joints can be limited. Patients with subacute osteomyelitis usually shows mild bony tenderness of several weeks, whereas fever and systemic symptoms are rarely accompanied.
In general, patients with chronic osteomyelitis complain of only chronic pain in the infected areas. Such patients could have mild fever. Bone defects, sequestration, osteosclerosis, and sinus tract formation are also common characteristics of chronic osteomyelitis [1]. Chronic osteomyelitis can be detected in a static state, but it can also slowly progress. In cases where there is obstruction of the sinus tract, local abscess or acute soft tissue infection are often identified.
4) Diagnosis
5) Treatment
(1) General principles of treatment (Fig. 2)
(2) Antimicrobial therapy (Table 6)
Table 6
Suggested regimens for antimicrobial therapy of osteomyelitis
aIn patients with delayed hypersensitivity to nafcillin, cefazolin can be used. In patients with immediate hypersensitivity, penicillins should be replaced by vancomycin or clindamycin. S. aureus isolates that are clindamycin-susceptible but erythromycin-resistant should be tested for inducible clindamycin resistance using the D-test.
bCombination therapy can be considered before the causative organism is identified in some conditions, i.e., preceding bacteremia when associated with urinary tract infection or intra-abdominal infection, or in the immunocompromised or elderly.
cThe trough concentration of vancomycin should be 15-20 µg/mL.
dCombination therapy with drugs to which the organism is susceptible should be used for the treatment of osteomyelitis caused by S. aureus. 500-750 mg ciprofloxacin every 12 houres + 600 mg rifampin every 24 houres/750 mg levofloxacin + 600 mg rifampin every 24 houres/trimethoprim/sulfamethoxazole 80/400 mg single strength, 2 tablets every 12 houres + 600 mg rifampin every 24 houres.
eQuinolone monotherapy is no longer considered adequate because of the high risk for the emergence of resistance during the high bacterial burden that exists in the initial stages of the disease; however, it can be used as an oral step down therapy after initial combination therapy with β-lactam agent and aminoglycoside.
(3) The role of adjuvant therapy
(4) Treatment of vertebral osteomyelitis
6) The role of adjuvant therapy
2. Septic arthritis
Septic arthritis is the major infectious disease in joints. However, because of its characteristics, most published studies involved a retrospective design or were case reports; as a result, it is difficult to develop clear clinical guidelines [11, 12]. However, it is critical that physicians are able to accurately distinguish septic arthritis from other conditions that have similar symptoms, such as joint pain, erythema, and swelling.
1) Epidemiology
The following are at high risk for septic arthritis: patients with degenerative osteoarthritis, people who abuse drugs, people with alcoholism, patients with diabetes, people receiving injections or acupuncture in their joints, people with skin ulcers, people aged 80 years or older, HIV patients, people of lower social and economic status, and those who have undergone arthroplasty surgery [13, 20] (Table 7). Current Korean studies are lacking, but some retrospective studies have reported that infections proceeding from joint acupuncture or intra-articular injections represent 50% of septic arthritis cases [19].
The number of patients with chronic illness who are in long-term care facilities has recently been increasing; consequently, the number of patients with septic arthritis has also increased. It is important to consider the possibility that patients living in medical facilities who have catheters, foot ulcers, drug addictions, or who have recently undergone orthopedic surgery may have contracted MRSA [21]. In the US and Europe in particular, the rates of community-associated MRSA (CA-MRSA) infections have been gradually increasing [22, 23]. In Korea, studies examining CA-MRSA have been conducted at multiple medical centers; however, only one case involved a patient with septic arthritis [24].
2) Distribution of causative pathogens
The most common causative pathogens are S. aureus and streptococci, which account for 60-90% of total septic arthritis cases (Table 8) [15, 16, 20, 25, 26]. In retrospective studies in Korea, 43 of 122 septic knee arthritis patients had positive culture results. Of those, 25 (58.1%) were due to S. aureus, while two (4.7%) were due to streptococci. Another Korean study reported that 20 of 80 patients had positive culture results; of those, 10 (50%) were due to S. aureus and four (20%) were due to CoNS [27]. Among young adults who engage in frequent sexual contact, arthritis can result from infection with gonococci, and septic arthritis with trauma can develop due to anaerobic pathogens [13, 28, 29, 30]. When risk factors such as old age, repeated urinary tract infections, recent abdominal surgery history, and immune suppression are present, infection with gram-negative bacilli should be considered [20, 31, 32]. Studies have found that between 4.5% and 64% of septic arthritis cases are culture-negative; the selection of antibiotics for such patients is difficult [19, 33].
3) Clinical opinions
Septic arthritis is associated with symptoms that include a sensation of heat, tenderness, and limited movement at the joint; in most cases, these characteristics progress rapidly within 2 weeks [15, 28]. In cases of low-pathogenic or tuberculous arthritis, symptoms can develop slowly; in arthroplasty infections, the symptoms are mostly acute, although it is possible that symptoms emerge slowly over an extended period [34]. Patients with septic arthritis can also exhibit systemic symptoms, such as fever [15]. Studies have reported that 60% of septic arthritis patients experience fever (over 37.5℃) [13, 15, 16, 35].
Septic arthritis usually occurs in the large joints, especially the knee and hip joints, which accounts for 60% of all cases of septic arthritis [20]. Shemerling and Jeng reported that in prospective studies, 8-27% of patients who complained of monoarticular heating sensation, tenderness, and edema had septic arthritis (according to bacterial culture results) [35, 36]. In most cases, the causative pathogens affected single joints, but approximately 22% of cases had multiple joint involvement. Gonococci and meningococci were the most common pathogens involved in infections in multiple joints [13, 16].
4) Diagnosis
Notes
1. Limitations
Causative pathogens and antibiotic sensitivities can vary according to geographical area and country; therefore, it is important to accumulate abundant data to allow the development of clinical guidelines reflecting the reality of each particular situation. However, these guidelines have been developed with limited data available for review because the domestic literature is scarce. It will be necessary to revise the guidelines after data from ongoing and future studies are analyzed. These treatment guidelines provide standards for the clinical treatment of patients, yet they do not represent an exclusive standard of care, as the treatments applied for each patient may differ depending on the opinion of each individual physician.
2. Plan for updating the guidelines
The plan is to revise these guidelines every three years. Based on the data collected between January 2013 and June 2016, we will update the guidelines with new content in 2016.
3. Potential conflicts of interest
The development of these treatment guidelines was supported by the Korean Society for Chemotherapy. However, the guideline development committee commits to maintaining its objectivity regardless of the origin of the funds provided. No other research funding was received while developing these guidelines. Moreover, no interest group influenced the development of these guidelines.
Supplement
We searched the PubMed (www.pubmed.gov) and KoreaMed (www.koreamed.org) databases for articles and guidelines published between January 1975 and December 2012 using the keywords "Arthritis, Infectious" [Mesh] or "septic arthritis" and "guideline" or "systematic". The committee assessed studies for potential eligibility and selected 138 articles from the literature.
Supplementary material
Guideline Korean version.
Supplementary material can be found with this article online http://www.icjournal.org/src/sm/ic-46-125-s001.pdf.

The Korean Society of Infectious Diseases, and The Korean Orthopaedic Association












