快樂小藥師 Im pharmacist nichts glücklich

The following test-and-teach case makes up an educational activity modeled on the interactive grand rounds approach. The questions within the case are designed to test your current (ie, baseline) knowledge. After each question, you will be able to see whether you answered correctly and can then read evidence-based information that supports the most appropriate answer choice. Please note that these questions are designed to challenge you; you will not be penalized for answering the questions incorrectly. At the end of the activity, there will be a short post-test assessment based on material covered in the case.

Patient History

Ben is a healthy 45-year-old man who was an accomplished high school athlete. He lettered in several varsity sports and played football at a small Midwestern college. Ten days ago he underwent an uncomplicated total arthroplasty of his left knee. On admission, he had a positive nasal swab for methicillin-resistant Staphylococcus aureus (MRSA) but he has no history of MRSA infection. His hospital course was uneventful and he was discharged on hospital day 4. Three days after discharge from the hospital he began outpatient rehabilitation and made good progress, eventually regaining full function of his knee.

Ben presents to a primary care clinic today for a previously scheduled wellness appointment. Although he has a follow-up appointment with his surgeon next week, Ben asks the primary care provider to look at his left knee. Last night, he noticed a small amount of clear drainage from the surgical site and he says that the area is redder than it was the day before. Ben's temperature is 98.6° F (37° C), blood pressure 140/88 mm Hg, and pulse 84 beats/min. On examination, the primary care provider observes minimal erythema around the incision with no swelling, tenderness, or fluctuance and notes a small area of dehiscence, from which a scant amount of purulent drainage is manually expressed. 

Q1:Staphylococcus aureus cellulitis is suspected. Which of the following organisms should also be considered as a possible cause of Ben's infection?

1. Group B Streptococcus
2. Group A beta-hemolytic Streptococcus
3. Cryptococcus neoformans
4. Haemophilus influenzae type B

Staphylococcus Aureus Infections in the Community

MRSA was first described in the medical literature in the 1960s.^[1] Initially, MRSA infections were detected only in hospitalized or recently hospitalized patients, those undergoing dialysis, residents of long-term care facilities, or intravenous drug users. Today, MRSA is the leading cause of nosocomial infections -- accounting for greater than 55% ofS aureus detected in hospitalized patients by the early 21st century -- and is the most common pathogen isolated from nosocomial SSTIs.^[2,3]

Since the 1960s, MRSA has undergone evolutionary changes and epidemiologic expansion,^[4] emerging in the community in the 1980s and rapidly becoming a source of infection in individuals without previously recognized risk factors. MRSA is currently characterized as healthcare-associated (HA-MRSA) or community-acquired (CA-MRSA), though currently these distinctions are epidemiologically blurred because the CA-MRSA phenotype is predominant in many healthcare settings.

From a practical standpoint, the characterization of HA-MRSA vs CA-MRSA is less important than identification of the most effective therapeutic approach. There are differences between CA-MRSA and HA-MRSA with respect to genetic composition, pathogenicity, and antibiotic susceptibility. Strains associated with recent CA-MRSA outbreaks were found to have unique microbiologic and genetic properties compared with traditional HA-MRSA strains. The virulence factor, such as Panton-Valentine leukocidin (PVL), a leukocyte-destroying exotoxin that causes tissue necrosis, is associated with certain CA-MRSA strains and may allow them to spread more easily and cause more skin disease. In addition to drug susceptibility patterns, molecular or genetic testing may be used more frequently in the future to distinguish strains of MRSA.

MRSA Colonization

The prevalence and clinical significance of MRSA colonization has been examined. Ellis and colleagues^[5] screened a large sample of US Army soldiers for S aureus colonization over time to characterize the natural history of CA-MRSA. At baseline screening, the MRSA and methicillin-susceptible S aureus (MSSA) colonization rates were 3% and 28%, respectively. During the study, of those who were MRSA-colonized, 38% developed an SSTI compared with 3% of those who were MSSA-colonized. A significant risk factor for baseline CA-MRSA colonization was antibiotic use within the previous 6 months. Furthermore, CA-MRSA colonization with PVL-positive strains was a significant risk factor for SSTI. More recently, Schechter-Perkins and colleagues^[6] assessed the prevalence of S aureus colonization at nasal and extranasal sites in patients presenting to an emergency department. Overall, 5% were found to be colonized with MRSA and 39% were found to be colonized with MSSA. Risk factors for MRSA colonization in this sample were HIV infection, diabetes, and participation in contact sports.

Q2:What is the recommended next step in the management of Ben's infection?

1. No treatment at this time, pending culture results
2. Empiric therapy for beta-hemolytic Streptococcus, pending culture results
3. Empiric therapy for MRSA, pending culture results
4. Incision and drainage

Purulent cellulitis is defined as cellulitis associated with purulent drainage or exudate in the absence of a drainable abscess.^[7] In the setting of preoperative colonization with MRSA and a significant incidence of MRSA infection in both the hospital and the community, empiric antibiotic therapy directed at MRSA is indicated pending culture results. A strain of CA-MRSA, USA 300, has emerged as a leading pathogen in cellulitis and other SSTIs.^[8] Empiric therapy for infection due to beta-hemolytic Streptococcus sp. is less likely to be necessary in this setting.^[7] Empiric therapy for beta-hemolyticStreptococcus sp. is recommended for patients with cellulitis without purulent drainage or exudate and no associated abscess.^[7]

MRSA and SSTIs

Klevens and colleagues^[9] conducted population-based surveillance for invasive MRSA disease at 9 sites participating in the Active Bacterial Core surveillance of the Emerging Infections Program Network from July 2004 through December 2005 to estimate the burden of invasive MRSA infections in the United States. The estimated number of people developing an invasive MRSA infection in 2005 was approximately 94,360, which was higher than previously reported estimates. Approximately 18,650 persons died during a hospitalization for an invasive MRSA infection. About 85% of all invasive MRSA infections were HA-MRSA; of those, about two thirds occurred outside of the hospital, while about one third occurred during hospitalization. About 14% of all invasive MRSA infections occurred in persons without obvious exposures to healthcare settings. Evaluation of the responsible pathogens confirmed that most of the associated MRSA strains were those that are traditionally associated with healthcare. However, the strains traditionally associated with transmission in the community are now being identified in healthcare settings.

In 2005, there were an estimated 14 million outpatient (provider offices, emergency, and outpatient departments) healthcare visits for suspected S aureus SSTIs in the United States.^[10] In 2004, approximately 76% of purulent SSTIs in adults seen in 11 emergency departments were caused by S aureus. Of these infections, 78% were caused by MRSA and, overall, MRSA caused 59% of all SSTIs.^[11]

Q3:A diagnosis of SSTI is made, a culture of the wound drainage is obtained, and a 10-day course of oral antibiotic is prescribed. Which antibiotic below is least likely to be active against MRSA?

1. Clindamycin
2. Trimethoprim-sulfamethoxazole (TMP-SMX)
3. Cephalexin
4. Linezolid

Historically, beta-lactam antibiotics have been the mainstay agents for empiric treatment of uncomplicated SSTIs. Beta-lactam antibiotics are a broad class of antibiotics that includes penicillin derivatives, cephalosporins, monobactams, and carbapenems. Cephalexin is a first-generation cephalosporin and, although commonly prescribed for uncomplicated SSTIs in the community, is not indicated in this case because, by definition, MRSA strains are resistant to penicillins and cephalosporins. Most MRSA strains are also resistant to erythromycin and other macrolides, such as azithromycin and clarithromycin. Unlike HA-MRSA strains, CA-MRSA strains remain susceptible to non-beta-lactam antibiotics.^[11,12]Clindamycin, TMP-SMX, long-acting tetracyclines such as doxycycline or minocycline, and linezolid are treatment options for oral empiric antibiotic therapy in the outpatient with an SSTI,^[7] though susceptibility to the chosen agent should be confirmed with microbiologic testing whenever possible.

Patient History (cont)

Four days after completion of the course of antibiotic, Ben calls his orthopaedic surgeon's office to report a fever of 101.4° F (38.5° C) that began the previous night. He is instructed to come in to the office immediately. In the orthopaedic surgeon's office, examination reveals a red, swollen, and very tender knee. A small amount of fluid is expressed at the incision site, which has an area of dehiscence. A prosthetic joint infection is suspected. Blood, exudate, and joint fluid aspirates (by arthrocentesis) are obtained and sent for culture, and Gram stains of wound exudate and joint fluid are performed. The orthopaedic surgeon suspects a complicated surgical site infection (SSI) with possible joint involvement.

Q4:Based on Ben's signs and symptoms, his SSI would be classified as:

1. Superficial incisional
2. Deep incisional
3. Superficial soft tissue
4. Organ/space

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Surgical Site Infections

An infection that occurs within 30 days at a surgical site or within 1 year of surgical implantation of a foreign body, such as an artificial heart valve or prosthetic joint, is by definition an SSI.^[13] Approximately 4%-5% of all inpatient surgeries performed in the United States are complicated by an SSI.^[14,15] SSIs are a major cause of morbidity; patients who develop an SSI are twice as likely to die during hospitalization compared with those who do not develop a surgical infection.^[16]

SSIs are categorized as superficial incisional, deep incisional, and organ/space.^[17] Superficial SSIs involve the skin and subcutaneous tissue of the incision; deep incisional SSIs involve the fascia and muscle. Superficial signs and symptoms such as erythema, dehiscence, tenderness, or discharge may also be present in patients with a deep incisional ororgan/space SSI. Although Ben's infection initially manifested superficially as a cellulitis, an organ/space infection must be ruled out due to his recent surgery for implantation of a prosthetic knee device. Infection is a serious complication of joint replacement that can result in both emotional and physical sequelae. Associated morbidity includes pain, loss of function, and potential removal of the prosthetic joint. Significant diagnostic and treatment resources are also required.^[18]

Organ/space SSIs usually do not occur until at least 1 week following surgery, but can present as late as months or years postprocedure if the implanted device remains in place.^[13] Infection that occurs less than 1 year after surgery is typically caused by introduction of bacteria at the time of the procedure. Infection that occurs more than 1 year after surgery is typically caused by hematogenous seeding of the prosthetic device during an episode of bacteremia that is unrelated to the surgery.^[19]

According to the American Academy of Orthopaedic Surgeons, evidence-based risk factors for device-related osteoarticular infection of the knee include a superficial SSI, operative time greater than 2.5 hours, immunosuppression, and prior joint infection.^[18] Although Ben had only 1 risk factor, a superficial SSI, his physical examination includes several findings associated with joint infection.

Patient History (cont)

Ben is admitted to the hospital for further management. The Gram stain of the wound exudate shows many polymorphonuclear leukocytes (PMNs) but no gram-positive organisms; the Gram stain of the joint fluid aspirate is positive for PMNs and gram-positive cocci. No loosening of the prosthesis is detected on examination or plain x-ray. Although prosthetic joint infections can be difficult to diagnose,^[18] the orthopaedic surgeon suspects a MRSA infection because of the rapidity of onset (Table 1), the patient's recent history of compatible skin infection, and his physical examination findings. However, it is important to confirm the diagnosis because missed diagnosis of a prosthetic joint infection contributes to inappropriate treatment and a high rate of prosthesis failure.

Table 1. Classification of Prosthetic Joint Infections by Onset

Data from Del Pozo JL, et al. N Engl J Med. 2009;361:787-794.^[20]

A medical student asks what the treatment plan is.

Q5:What is the most appropriate answer?

1. The patient will be treated with a longer course of parenteral antibiotics, without debridement
2. The joint space will be surgically debrided in 1 week, followed by parenteral antibiotic therapy
3. The joint space will be debrided and drained with retention of the prosthesis and an additional course of parenteral antibiotics
4. The joint exudate will be recultured in 1 week

Management of Prosthetic Joint Infections

Debridement with device removal is recommended when the implant is unstable (ie, the bone-cement interface is loose), the duration of symptoms is greater than 3 weeks, and/or the onset of infection is greater than 2 months after surgery.^[7]The prosthetic device can be retained when infection occurs less than 2 months after joint replacement, symptoms have been present for 3 weeks or less, the implant is stable, and any associated soft-tissue abscesses have been debrided.^[7]Regardless of the intervention, antimicrobial therapy should be guided by the results of intraoperative cultures of synovial fluid, tissue, and bone.

Q6:After appropriate surgical management has been accomplished, which of the antibiotic therapies below is most appropriate for the management of Ben's infection?

1. Parenteral therapy plus oral rifampin therapy
2. Parenteral therapy alone
3. Parenteral therapy plus oral rifampin therapy followed by long-term oral suppressive therapy
4. Parenteral therapy followed by long-term oral suppressive therapy

Patient History (cont)

Ben was taken to the operating room for immediate debridement of the prosthetic joint and surrounding soft tissues. Open-joint intraoperative cultures were obtained, the joint and surrounding tissues were washed out, and the joint polyethylene liner was replaced. Cultures of surgical wound exudate obtained earlier by both the primary care provider and the orthopaedic surgeon and the blood cultures obtained by the orthopaedic surgeon have all been reported as negative. However, cultures of joint fluid aspirates obtained in the outpatient setting and intraoperatively are positive for MRSA.

Q7:Parenteral antibiotic therapy plus oral rifampin for 2 weeks followed by oral suppressive therapy for 6 months is indicated. Which of the following parenteral antibiotics is not appropriate for initiation of therapy?

1. Doxycycline
2. Daptomycin
3. Vancomycin
4. Linezolid

Vancomycin has been the cornerstone of the treatment of serious S aureus infections since the emergence of MRSA in the early 1980s. There is increasing evidence that proper dosing of vancomycin has an impact on outcomes in serious MRSA infections.^[21,22] Although vancomycin, TMP-SMX, clindamycin, linezolid, daptomycin, telavancin, tigecycline, and ceftaroline all have activity against and are approved to treat MRSA infections at other sites, none are specifically indicated by the US Food and Drug Administration for the treatment of prosthetic joint infections. As stated above, a new guideline on the management of prosthetic joint infections is under development by the IDSA and is expected to further address these recommendations.

Patient History (cont)

Joint and tissue debridement are done and the prosthesis is retained. Antibiotic therapy with intravenous vancomycin plus rifampin is begun postoperatively. Ben has been afebrile since postoperative day 2 and is discharged on postoperative day 5. His discharge orders include outpatient intravenous vancomycin plus oral rifampin twice daily for the remainder of a 2-week course, and he is told that he will be on oral antibiotic therapy with 2 drugs for approximately 6 months after completion of the vancomycin/rifampin therapy.

Initially Ben has a good clinical response, including progressive healing at the surgical site, decreasing swelling and tenderness, and absence of drainage. After completion of parenteral antibiotic therapy and 3 weeks into oral suppressive therapy, Ben's left knee becomes red, swollen, and painful. The knee incision begins draining serosanguinous fluid. His temperature spikes to 101° F (38.3° C). The susceptibility studies on the isolates of S aureus from the knee drainage show that the minimum inhibitory concentration (MIC) of vancomycin for this S aureus isolate is 4 µg/mL.

Q8:Which of the following treatment decisions is most appropriate?

1. Increase the vancomycin dosage
2. Redebridement
3. Remove the joint prosthesis
4. Switch to daptomycin therapy

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Treatment Failure

Although surgical debridement and retention of the joint prosthesis may be the preferred initial treatment approach in some patients to avoid the potential morbidity associated with excision arthroplasty (eg, an elderly or debilitated patient with a stable prosthesis), success rates with this approach are variable and success is more likely when the infection is caused by a relatively avirulent organism.^[23] While the overall success rate of the debridement/retention strategy may be as high as 60% at 2 years, the organism-specific rates vary widely and should probably guide decision-making. The 2-year infection-free rate in the S aureus prosthetic joint infection group in 1 study was 22%.^[23] In this case, the patient was relatively young and healthy and his infection was caused by MRSA, a relatively virulent organism. Risk factors independently associated with treatment failure include the presence of a sinus tract or longer duration of symptoms.^[24]

From MRSA to VRSA

In recent years, strains of S aureus with reduced susceptibility to vancomycin have begun to emerge. The increased prevalence of MRSA has led to widespread use of vancomycin, with the potential for decreased susceptibility to vancomycin manifested as increased MIC, also referred to as "MIC creep." In 2006, the Clinical and Laboratory Standards Institute, the group that establishes breakpoints for resistance or susceptibility that inform the results from the microbiology laboratory, changed the vancomycin MIC breakpoints for S aureus.^[25] The current breakpoints are shown in Table 2. When the MIC is ≤ 1 μg/mL, vancomycin is considered effective; when the MIC is > 1 μg/mL, vancomycin is considered less effective. The role of vancomycin in the treatment of CA-MRSA and HA-MRSA SSTIs has also become less reliable due to concerns about slow bactericidal activity.^[7] Vancomycin has also been shown to have limited penetration into bone,^[26] with reported failure rates of 35%-46%.^[27-30]

Table 2. Vancomycin MIC Breakpoints for S aureus

Patient History (cont)

Ben is scheduled for arthroplasty with a 2-stage prosthesis exchange. His prosthetic joint is removed and a nonarticulating spacer is inserted. Joint culture specimens taken intraoperatively again test positive for MRSA that has a vancomycin MIC of 2 μg/mL but is fully susceptible to daptomycin.

He is discharged on postoperative day 7 and prescribed 6 weeks of daily parenteral daptomycin at a dose of 6 mg/kg plus oral rifampin 300 mg twice daily. Because relapse may be related to inadequate debridement (eg, retained cement and/or infected bone) rather than antibiotic resistance, a period of antibiotic-free observation was recommended. One month after completion of the antibiotic course, a new prosthetic joint is implanted.

Are MRSA Screening and Decolonization Relevant to This Case?

The importance of MRSA screening to diminish the risk for postoperative MRSA SSIs (not SSTIs) in orthopaedic surgery has been documented,^[30] and though mupirocin is frequently used to prevent recurrent CA-MRSA SSTI, there is no evidence to support decolonization as a means of preventing hematogenous seeding of a joint prosthesis.

Summary

Infection is one of the most feared complications of joint arthroplasty, occurring in 0.5%-2.0% of episodes with an estimated cost of diagnosis and treatment of $30,000-$50,000 per episode.^[31] This case demonstrates the individual burden and complexities of management of S aureus prosthetic joint infections. Diagnosis requires a high index of suspicion. Management requires aggressive surgical debridement and appropriate antimicrobial selection to address susceptibility patterns. The spectre of burgeoning antimicrobial resistance among strains of this virulent pathogen, manifested by phenomena such as MIC creep (the emergence of strains with reduced vancomycin susceptibility) and severe disease in individual patients serves as a clarion call to conserve antimicrobial resources through stewardship efforts. Selection of agents with the narrowest possible spectrum of activity, appropriate formulary management, and close collaboration with the microbiology laboratory are necessary to help slow the rise of resistance inside and outside healthcare facilities.

What began as an uncomplicated knee arthroplasty with normal postoperative recovery became a potentially life-threatening osteoarticular infection. This case illustrates the problem of endogenous SSI in which bacteria were introduced at the time of surgery, the importance of beginning early empiric antibiotic therapy, initiation of pathogen-specific therapy once culture data are available, and the pivotal role of surgical management of deep-seated infections.

In hospitals with a significant incidence of S aureus with a vancomycin MIC of 1 µg/mL or 2 µg/mL, clinicians might consider empiric treatment with agents other than vancomycin until susceptibility data for individual isolates are known (Table 3 and Table 4). The phenomenon of MIC creep played a large role in Ben's care; susceptibility studies on the isolates of S aureus in the fluid from his knee revealed a vancomycin MIC for S aureus of 2-4 µg/mL. This guided the treatment in his case to removal of the prosthesis and systemic antibiotic therapy with an alternative to vancomycin.

Table 3. IDSA Recommendations for the Treatment of Skin and Soft-Tissue Infections Due to Methicillin-Resistant Staphylococcus aureus in Adults

CA-MRSA = community-acquired methicillin-resistant Staphylococcus aureus; PO = oral; TID = 3 times daily; TMP-SMX = trimethoprim-sulfamethoxazole; DS = double-strength; BID = twice daily; QID = 4 times daily; QD = once daily; SSTI = skin and soft-tissue infection; IV = intravenous; ND = no data 

^aFor patients with normal renal and hepatic function
^bFor information on the process used to determine the strength of recommendations (A-C) and quality of evidence (I-III), refer to the original guideline document.
^cConditions in which antimicrobial therapy is recommended after incision and drainage of an abscess due to CA-MRSA: (1) severe or extensive disease (eg, involving multiple sites of infection) or rapid progression in the presence of associated cellulitis; (2) signs and symptoms of systemic illness; (3) associated comorbidities or immunosuppression (diabetes mellitus, HIV infection/AIDS, neoplasm); (4) extremes of age; (5) abscess is located in an area that is difficult to drain completely (eg, face, hand, genitalia); (6) associated septic phlebitis; and (6) lack of response to incision and drainage alone.
Data from Liu K, et al. Clin Infect Dis. 2011;52:1-33.^[7]

Table 4. IDSA Recommendations for the Treatment of Bone and Joint Infections Due to Methicillin-ResistantStaphylococcus aureus in Adults

IV = intravenous; QD = once daily; BID = twice daily; PO = oral; SS = single-strength; DS = double-strength; TMP-SMX = trimethoprim-sulfamethoxazole; TID = 3 times daily; ND = no data 

^a For patients with normal renal and hepatic function.
^bFor information on the process used to determine the strength of recommendations (A-C) and quality of evidence (I-III), refer to the original guideline document.
Data from Liu K, et al. Clin Infect Dis. 2011;52:1-33.^[7]

Supported by independent educational grants from Astellas, Cubist, and Pfizer.

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