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Treatment of prosthetic joint infections

Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Treatment of prosthetic joint infections Authors Elie Berbari, MD, FIDSA Larry M Baddour, MD, FIDSA Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2012. | This topic last updated: Jan 9, 2012. INTRODUCTION Periprosthetic joint infection occurs in 1 to 2 percent of joint replacement surgeries and is one of the leading causes of arthroplasty failure [1-3]. The issues relating to the medical and surgical treatment of prosthetic joint infections (PJIs) will be reviewed here. Infections associated with other implanted orthopedic devices, such as pins and rods, will not be specifically discussed but similar principles apply [1]. The pathogenesis, clinical manifestations, and prevention of these infections are discussed separately. (See "Clinical manifestations and diagnosis of prosthetic joint infections" and "Prevention of prosthetic joint infections".) TIMING OF INFECTION Prosthetic joint infections (PJIs) are categorized according to the timing of symptom onset after implantation: early-onset (<3 months after surgery), delayed-onset (from 3 to 12 months after surgery), and late-onset (>12 months after surgery). These infections have the following characteristics [4]: Early-onset infections are usually acquired during implantation and are often due to virulent organisms, such as S. aureus, gram-negative bacilli, anaerobic organisms, or mixed infections [1,4]. Delayed-onset infections are also usually acquired during implantation. Consistent with the indolent presentation, delayed infections are usually caused by less virulent organisms, such as coagulasenegative staphylococci (CoNS) or enterococci. Late-onset infections typically result from hematogenous seeding. S. aureus, beta hemolytic streptococci, and Enterobacteriaceae are responsible for most infections. GENERAL PRINCIPLES OF THERAPY Treatment of prosthetic joint infections (PJIs) usually involves both medical and surgical measures [5]. The type and timing of such therapies is dependent upon the cause and timing of the infection, and the condition of the host. Biofilms play an important role in the pathogenesis of PJIs. Organisms within biofilm become resistant to therapy; as a result, antimicrobial therapy is often unsuccessful unless the biofilm is physically disrupted or removed by surgical debridement. Biofilms also account for two other features of PJIs: the propensity of these infections to become apparent weeks or months after surgery, and the common observation that antimicrobial therapy results in a clinical response that is typically followed by a relapse within days or months if the infected prosthesis is retained. (See "Clinical manifestations and diagnosis of prosthetic joint infections", section on 'Biofilm'.) A small number of patients with PJIs ultimately require amputation for control of the infection. Common factors that lead to amputation include severe bone loss, intractable pain, and multiple failed revision attempts [6]. Early-onset infections Debridement and retention of the prosthesis may be appropriate for patients with early onset PJI with a well-fixed prosthesis in the absence of a sinus tract. Surgical debridement followed by a long course of parenteral antibiotics is curative in up to 71 percent of early-onset infections [7-9]. Section Editor Daniel J Sexton, MD Deputy Editor Elinor L Baron, MD, DTMH

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Delayed-onset and late-onset infections The majority of delayed-onset and late-onset infections require prosthesis removal [10]. Debridement alone is insufficient treatment if the prosthesis is both infected as well as loose; in such cases replacement arthroplasty is required. Replacement arthroplasty Options for replacement arthroplasty in patients with PJIs include one-stage or two-stage procedures. The one-stage procedure is more commonly performed in Europe [4], while the twostage procedure is preferred in the United States [11,12]. One-stage A one-stage or direct exchange strategy procedure requires resection of the infected joint, debridement of the soft tissue and bone, and reimplantation of a new procedure during the same surgery. This procedure can be considered in patients with a total hip arthroplasty infection who have a good soft tissue envelope and an easily treatable microorganism. In selected case series, the success rate of this procedure is close to 80 percent [13]. Given the lack of comparative effectiveness trials, it is difficult to recommend this procedure over the standard two-stage approach [14-18]. Based on published literature, a one-stage approach may be suitable in highly selected patients [19]. Two-stage A two-stage exchange strategy is the most common surgical procedure performed in the United States for management of PJI. This approach entails resection of the infected prosthesis, debridement of soft tissue and bone, and placement of an antimicrobial-impregnated spacer [11,20]. Following removal of the infected prosthesis, parenteral antibiotics with activity against the infecting organism(s) are administered for four to six weeks. Reimplantation of a prosthesis is undertaken following completion of antibiotic therapy. The success rate of two-stage exchange arthroplasty is close to 90 percent [12,21-23], although most studies excluded patients who had a permanent resection arthroplasty without a second-stage reimplantation, usually due to persistent infection in the joint or periarticular tissues [12,23,24]. In addition, the published duration of follow-up has varied widely; therefore, it is difficult to use published success rates to predict the outcome in individual patients. Many experts favor an observation period off of antibiotics prior to implantation of a new prosthesis (to increase the sensitivity of culture results obtained at the time of implantation), while others favor proceeding directly with implantation of a new prosthesis following completion of antibiotics if there are no clinical signs of infection [25]. In general, it is appropriate to obtain follow-up cultures prior to implantation of a new prosthesis in selected patients, particularly those with difficult-to-treat organisms such as methicillin-resistant staphylococci, Pseudomonas species, or enterococci. Because this strategy requires a delay prior to new device implantation, it is not routinely recommended. This approach was evaluated in a nonrandomized study including 69 patients with knee arthroplasty infection treated with two-stage replacement arthroplasty; 35 had joint replacement immediately after completing six weeks of antimicrobial therapy, while 34 had repeat culture four weeks after completion of antimicrobial therapy prior to joint replacement [23]. Those with positive cultures underwent repeat debridement and a repeat course of antibiotic therapy prior to joint replacement; those with negative cultures underwent prompt joint replacement. The rate of recurrent infection was lower in the patients who underwent repeat cultures than those that did not (3 versus 14 percent) [23]. In another study including 152 patients with PJI, the presence of positive cultures obtained at the time of new prosthesis implantation was not associated with a worse outcome [26]. Options are limited for patients who are functionally impaired, have significant medical or surgical comorbidities, have poor bone stock or soft tissue coverage, or cannot undergo a prolonged course of appropriate antimicrobial therapy. Patients with total hip arthroplasty may undergo permanent resection arthroplasty without arthrodesis (Girdlestone procedure). Patients with total knee arthroplasty may undergo permanent resection with arthrodesis. If surgery is not possible, long-term antimicrobial suppression may be warranted [13]. Arthrodesis Arthrodesis may be needed for patients unable to undergo replacement arthroplasty. The surgical approach depends on individual circumstances. In some cases, external fixation devices or placement of an internal fixator, such as a long arthrodesis nail, may be required [27]. When successful, this procedure usually provides excellent pain relief. However, it may have significant functional drawbacks, such as leg length discrepancy and difficulty in performing daily activities, including walking. Arthrodesis may be difficult to perform in patients with extensive osteomyelitis, osteolysis, or extensive loss of
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cancellous or cortical bone. Amputation may be the only available option in these cases; the outcome of patients undergoing this procedure is generally poor. ANTIBIOTIC THERAPY The goal of antibiotic therapy in patients with prosthetic joint infections (PJIs) is to cure or control the infectious process. There is a paucity of randomized controlled trials that have examined the efficacy of medical therapy in patients with PJIs. The literature on this issue consists almost exclusively of retrospective case series in which widely different regimens and durations of therapy are reported. Empiric antibiotic therapy Empiric antibiotic therapy may be justified in the rare instance in which a patient with a PJI presents with sepsis or is otherwise too unstable to wait for culture and sensitivity results. However, in most cases it is preferable to delay antibiotic therapy until specimens are obtained by joint aspiration, joint debridement, and/or prosthesis removal. The selection of specific antimicrobial regimens depends on a number of factors including the results of in vitro susceptibility data, patients allergies and intolerances, patients preferences, and the type of surgical procedure preformed. Pathogen-specific antibiotic therapy Most patients require a four to six week course of parenteral antimicrobial therapy following surgery. In patients treated with debridement and retention, parenteral antimicrobial therapy is typically followed by a long-term course of oral antimicrobial therapy, the duration of which varies and is dependent on several factors (as outlined below). Staphylococci Nafcillin or oxacillin (2 g intravenously every four to six hours) is the most effective therapy against methicillin-sensitive S. aureus (MSSA). Cefazolin (1 to 2 g intravenously every eight hours) may be used as an alternative. Retrospective data suggests that ceftriaxone (2 g intravenously every 24 hours) may be as effective as other antistaphylococcal beta-lactams for treatment of oxacillin susceptible staphylococcal PJIs [26,28]. Patients with a history of type I allergy (anaphylaxis) to penicillin can be treated with either clindamycin (900 mg intravenously every eight hours) or vancomycin (30 mg/kg daily intravenously in two divided doses to a maximum dose of 2 g/day). Methicillin-resistant S. aureus (MRSA) infection should be treated with vancomycin; daptomycin or linezolid can be used as alternative agents [29-31]. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults" and "Vancomycin dosing and serum concentration monitoring in adults".) Treatment regimens for CoNS are identical to those for S. aureus. However, most strains of CoNS that cause PJI are methicillin-resistant. Role of rifampin In general, the indication for use of rifampin is staphylococcal PJI treated with debridement and retention of the prosthesis. This is discussed further below. (See 'Following debridement with retention of prosthesis' below.) Streptococci The treatment of choice for streptococcal PJIs is penicillin (12 to 18 million units/day in four divided doses) or ampicillin (2 g every six hours) [32]. Ceftriaxone (1 to 2 g intravenously every 24 hours) is an acceptable alternative agent and may be used for dosing convenience. Patients allergic to penicillin may be treated with clindamycin (900 mg intravenously every eight hours) or vancomycin (30 mg/kg daily intravenously in two divided doses to a maximum dose of 2 g/day). The outcome of PJI due to penicillin-susceptible streptococci treated with debridement and prolonged antibiotic therapy is generally good. In one retrospective series, the cumulative risk of relapse in patients who underwent debridement early after onset of symptoms was 11 percent [32]. Enterococci Enterococcal PJIs are rare, and it can be difficult to distinguish between true infection and culture contamination. If cultures demonstrating enterococcus are felt to represent true infection, selection of antibiotic therapy should be tailored to susceptibility results (table 1). In a retrospective review of 47 patients, there was no difference in outcome between patients receiving combination and those receiving monotherapy [33]. (See "Treatment of enterococcal infections".) Gram-negative bacilli Gram-negative bacilli cause 15 percent of all first-time episodes of PJIs. Patients
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with gram-negative infections tended to be older, to develop infections earlier after surgery, and to have worse outcome with prolonged antibiotic therapy and debridement than patients with gram-positive PJIs [10]. Gram-negative bacilli that are susceptible to fluoroquinolones can usually be treated orally with an agent, such as ciprofloxacin (500 to 750 mg twice daily). Patients with PJIs due to P. aeruginosa are extremely difficult to cure even with debridement and prosthesis removal. One of the following regimens may be used: Ciprofloxacin (750 mg orally twice daily) if the isolate is susceptible An antipseudomonal beta-lactam antibiotic such as ceftazidime (2 g intravenously every eight hours) or piperacillin (3 g intravenously every six hours) An antipseudomonal beta-lactam antibiotic PLUS an aminoglycoside such as gentamicin or tobramycin (dose for peak serum concentration of 5 to 10 mcg/mL and trough levels below mcg/mL) Anaerobes Prosthetic hip or knee infections due to anaerobes are relatively uncommon; shoulder infections due to P. acnes are the most common presentation of anaerobic PJI. Options for treatment of infection due to Propionibacterium acnes include penicillin (24 million units intravenously every 24 hours given in six equally divided doses or as continuous infusion) or ceftriaxone (1 to 2 g intravenously once daily). Vancomycin and clindamycin are also active against most Propionibacterium acnes isolates. Metronidazole (500 mg orally three times a day) may be used for other types of anaerobic infections that are susceptible to this agent.(See "Invasive Propionibacterium infections".) Mycobacterium tuberculosis PJIs due to M. tuberculosis can sometimes be cured without joint removal if the infection is recognized early [34]. (See "Skeletal tuberculosis".) Fungi Fungal PJIs are difficult to cure with medical therapy alone. As a result, most such patients require prosthesis removal and arthrodesis to resolve their infections. However, patients with infections sensitive to azole antifungal agents can sometimes be cured or suppressed after debridement if a long (three to six months) course of therapy is undertaken. (See "Candida osteomyelitis and arthritis".) Culture negative A small proportion of patients with PJIs have negative cultures. In a review of 897 episodes of PJIs, 7 percent of patients had culture-negative PJI; about one-half of these patients had received prior antibiotics [35]. Patients with culture-negative PJIs should receive antimicrobial agents with activity against gram-positive and gram-negative pathogens. Suggested regimens include vancomycin with ciprofloxacin or cefazolin with ciprofloxacin at the doses outlined above. Patients with culture negative PJI have similar outcomes as patients with positive cultures following standard treatment regimens [26,35]. In one retrospective study including 60 patients with PJI and negative cultures, fiveyear survival free of treatment failure was 94 percent in patients treated with two-stage exchange arthroplasties and 71 percent in patients who underwent debridement with retention of their prosthesis [35]. Following excision arthroplasty We generally recommend four to six weeks of parenteral antibiotic therapy in patients undergoing excision arthroplasty before the second stage replacement arthroplasty is performed. The antibiotic can often be given in the outpatient setting preferably using a peripherally-placed central venous catheter (PICC line) or a tunneled central vascular catheter. The specific antibiotic used depends upon the infecting organism and is therefore critically dependent upon a definitive microbiologic diagnosis. (See "Clinical manifestations and diagnosis of prosthetic joint infections".) Following debridement with retention of prosthesis Debridement, polyethylene liner exchange, and retention of prosthesis is the favored surgical approach in patients with acute or early PJI, in the setting of a well fixed prosthesis and in the absence of a sinus tract. For elderly patients with infected total hip arthroplasty and a fixed prosthesis, debridement and retention with long-term antibiotic suppression may be a reasonable approach compared with debridement and exchange arthroplasty, which may result in a higher rate of relapse-free survival but is associated with substantial postoperative morbidity and mortality [36]. Arthroscopic debridement without polyethylene liner exchange and retention of prosthesis with intravenous antimicrobial therapy followed by longterm suppression may also be effective in some patients with early-onset prosthetic knee infections [24].
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The duration of antibiotic therapy following debridement and retention of the prosthetic joint is not well standardized. The clinical approach depends in part on the causative organism and individual patient circumstances including the duration of infection, the stability of the prosthesis, and concomitant medical conditions. Many favor treating for two to six weeks with parenteral therapy, followed by oral therapy for an extended duration of time. Suppressive oral antibiotic therapy typically postpones rather than prevents treatment failure [7,26,37]. Some patients on suppressive therapy eventually develop septic loosening of the prosthesis; a minority develops frank purulence in the joint space or sepsis. Patients with staphylococcal PJI managed with debridement and retention of prosthesis may benefit from use of a rifampin-based regimen [9]. Rifampin can penetrate deep into biofilm associated with prosthesis retention. Some favor administering rifampin (300 to 450 mg orally twice daily) together with an antistaphylococcal beta lactam agent or vancomycin for initial treatment (two to six weeks), followed by subsequent management with three to six months of oral rifampin in combination with either ciprofloxacin or levofloxacin [4,8,9,31,38]. The efficacy of this approach was evaluated in a study of 33 patients with early onset staphylococcal PJI managed with debridement and retention of prosthesis and randomized to receive two weeks of parenteral antibiotic therapy, followed by oral ciprofloxacin plus rifampin or ciprofloxacin alone for three to six months [8]. A significantly higher cure rate was observed among those who treated with ciprofloxacin-rifampin than those treated with ciprofloxacin alone (100 versus 58 percent). Twenty-six patients had S. aureus infection (none methicillin-resistant) and seven had S. epidermidis infection (two methicillin-resistant); patients received two weeks of parenteral antibiotic therapy with flucloxacillin or vancomycin with or without oral rifampin. The success rate in the absence of rifampin for cases of prosthesis retention in staphylococcal PJI is typically 50 to 60 percent [12,13,37,39,40]. Risk factors independently associated with treatment failure include the presence of a sinus tract and symptom duration of 21 days or more prior to debridement of [37]. Clinical approach Debridement and retention of the prosthesis may be appropriate for patients with acute infection in the absence of prosthesis loosening or sinus tract who are treated within 30 days of the onset of symptoms. Such patients should be treated with a prolonged course of antimicrobial therapy (four to six weeks), followed by oral therapy (with inclusion of rifampin if feasible) for three to six months. Oral agents should be tailored to susceptibility data; options include cephalexin, clindamycin, dicloxacillin, an oral fluoroquinolone, or trimethoprim-sulfamethoxazole. Suppressive oral antibiotic therapy may be warranted indefinitely. Caveats to rifampin use include infection with S. aureus strains with in vitro resistance to fluoroquinolones or rifampin (since resistance can emerge readily during therapy in such circumstances), and drug interactions and toxicity. Rifampin has significant drug interactions and risk of toxicity in patients with preexisting liver disease; careful consideration of an individual's other medications and medical history (particularly history of liver disease) is required prior to initiation of rifampin. (See "Rifampin (rifampicin): Patient drug information".) Suppressive therapy Long-term suppressive therapy in the absence of surgical debridement is sometimes necessary in patients who are elderly, have contraindications to general anesthesia, or refuse to allow removal or debridement of an infected prosthesis. Suppressive therapy may be unsuccessful [41]. Antibiotic impregnated cement Antibiotic impregnated cement can be used for one- and two-stage joint replacement procedures [42-44]. Types of cement spacers include static spacers (blocks and beads) and mobile or articulating spacers. In one meta-analysis, the use of antibiotic-impregnated cement lowered the infection rate by approximately 50 percent in primary hip arthroplasty (2.3 versus 1.3 percent) [45]. The optimal approach to use of antibiotic impregnated cement is uncertain; randomized studies are needed to determine the best types of spacers, antibiotics, and mixing techniques for total knee and total hip arthroplasties. OUTCOME A retrospective analysis of 200 first episodes of prosthetic joint infection (PJI) in patients with rheumatoid arthritis between January 1969 and December 1995 assessed rates of five-year survival free of treatment failure [40]. In multivariate analysis, the type of surgical procedure was the only variable that was associated with treatment failure. The rates of five-year survival free of treatment failure were by surgical procedure: Two-stage exchange - 79 percent (95% CI, 66-93 percent) Resection arthroplasty - 61 percent (95% CI, 49-74 percent) Debridement with retention of components - 32 percent (95% CI, 21-49 percent)

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Limitations in the study include those related to the retrospective nature of the study (eg, no established treatment protocol, no randomization, inability to assess all potential variables) and the differences in surgical modalities used over the 27 years covered by the analysis. Risk factors that predispose to treatment failure were identified in a retrospective study of 99 episodes of PJI in patients treated with debridement and retention of components [37]. The median duration of intravenous antimicrobial therapy was 28 days followed by oral suppression for a median duration of 541 days. The two-year survival rate free of treatment failure was 60 percent. A multivariable analysis identified the presence of a sinus tract (hazard ratio [HR], 2.84; 95% CI, 1.48-5.44) and a duration of symptoms prior to debridement of 8 days (HR, 1.77; 95% CI, 1.02-3.07) as associated with an increased risk of treatment failure. In addition, outcomes for methicillin-resistant S. aureus (MRSA) PJIs are often poor, with treatment failure rates as high as 38 percent [46]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Knee replacement (The Basics)" and "Patient information: Hip replacement (The Basics)") Beyond the Basics topics (see "Patient information: Joint infection (Beyond the Basics)" and "Patient information: Total hip replacement (arthroplasty) (Beyond the Basics)" and "Patient information: Total knee replacement (arthroplasty) (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Treatment of infection associated with prosthetic joints is not standardized, because of the variable clinical presentations and the lack of data from randomized, controlled trials. (See 'General principles of therapy' above.) Treatment should commence immediately after the onset of symptoms of infection to increase the probability of success. (See 'General principles of therapy' above.) Treatment of prosthetic joint infections (PJIs) usually involves surgical debridement followed by a prolonged course of intravenous antibiotics. (See 'General principles of therapy' above.) The selection of specific antimicrobial regimens depends upon the infecting organism and is therefore critically dependent upon a definitive microbiologic diagnosis. (See 'Antibiotic therapy' above.) Two-stage replacement arthroplasty is associated with the highest success rates and is recommended in patients who are able to tolerate the long period of immobilization. (See 'Replacement arthroplasty' above.) Arthrodesis (fusion of the joint) is the treatment of choice for patients with poor skin coverage and inadequate tissue to provide a functional arthroplasty. (See 'Arthrodesis' above.) Debridement and retention of a prosthesis is successful in selected staphylococcal PJI cases treated with a prolonged rifampin-based regimen or in acute streptococcal PJI. (See 'Clinical approach' above.) Long-term suppressive therapy alone is sometimes necessary in patients who are elderly, have
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Treatment of prosthetic joint infections

contraindications to general anesthesia, or refuse to allow removal or debridement of an infected prosthesis. (See 'Suppressive therapy' above.) ACKNOWLEDGMENT The editorial staff at UpToDate, Inc. would like to acknowledge Dr. Don Goldenberg, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 7665 Version 10.0

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Treatment of prosthetic joint infections

GRAPHICS
Parenteral therapy for susceptible enterococci
Regimen
Preferred options for monotherapy* Ampicillin Penicillin G Vancomycin 6-12 g per 24 hours in 4 to 6 equally divided doses 18-30 million units per 24 hours either continuously or in 6 equally divided doses 30 mg/kg per 24 hours in 2 equally divided doses

Dosage and route

Options for combination therapy: One of above agents, PLUS one of the following agents (for bactericidal activity) Gentamicin Streptomycin 3 mg/kg per 24 hours in 3 equally divided doses 15 mg/kg per 24 hours in 2 equally divided doses

* Daptomycin and tigecycline are also approved for use in complicated skin and skin structure infections due to vancomycin-susceptible E faecalis; in addition, tigecycline has approval for complicated intraabdominal infections associated with E. faecalis. Infections due to beta lactamase producing enterococci requiring parenteral therapy may be treated with ampicillin-sulbactam (12 g per 24 hours) or vancomycin. Synergistic activity of a cell wall-active agent in combination with gentamicin or streptomycin is required for bactericidial activity, which is warranted in the setting of invasive infections such as endocarditis, meningitis, and bacteremia in the setting of valvulopathy and/or critical illness. When combination therapy with an aminoglycoside is precluded by high-level resistance to both gentamicin and streptomycin, ceftriaxone in combination with ampicillin could be considered. (See "Antimicrobial therapy of native valve endocarditis" section on Enterococcus). In patients with normal renal function, gentamicin dosing should be adjusted to achieve a 1hour serum concentration of 3 mcg/mL and a trough concentration of <1 mcg/mL. In patients with normal renal function, streptomycin dosing should be adjusted to achieve a 1-hour serum concentration of 20 to 35 mcg/mL and a trough concentration of <10 mcg/mL.

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