The prevalence of multidrug resistance in gram-positive

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1 Early Switch From Vancomycin to Oral Linezolid for Treatment of Gram-Positive Heart Valve Endocarditis Andrea Colli, MD, Riccardo Campodonico, MD, and Tiziano Gherli, MD Department of Cardiac Surgery, University of Parma, Parma, Italy Background. Patients with complicated gram-positive endocarditis are usually treated with a combination of surgical procedure and long-term antibiotic therapy with intravenous vancomycin. However, oral linezolid offers the potential for an early switch from intravenous vancomycin to oral linezolid therapy. Methods. We conducted a retrospective study from February 2002 to August 2005 to determine the potential for early switch from intravenous vancomycin to oral linezolid in patients surgically treated for a left-sided active gram-positive endocarditis. Results. Fourteen patients were identified; average age was years. There were 10 (85%) and 2 (15%) cases of native and prosthetic valve endocarditis, respectively. Patients were operated on 3 to 10 days after diagnosis. There were no cases of operative mortality. Mean follow-up was months. Two (14%) patients died of noncardiac causes during follow-up. The mean intensive care unit length of stay was days, and mean hospital length of stay was days. No cases of recurrent endocarditis or periprosthetic leakage were observed. Conclusions. The combination of aggressive surgical treatment and the early switch from intravenous vancomycin to oral linezolid for treatment of active grampositive heart valve endocarditis is safe and effective, and reduces infection relapses, vancomycin use, hospital length of stay, and economic costs. (Ann Thorac Surg 2007;84:87 91) 2007 by The Society of Thoracic Surgeons Accepted for publication Feb 26, Address correspondence to Dr Colli, Department of Cardiovascular Surgery, Hospital Clinic, C. Villaroel 170, Barcelona, 08036, Spain; colli.andrea@libero.it. The prevalence of multidrug resistance in gram-positive bacteria is rapidly increasing. The worldwide management of infections attributable to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci, and penicillin-resistant Streptococcus pneumoniae is increasingly difficult to manage with available therapies [1]. Staphylococcal intermediate [2, 3] and full resistance [4] to vancomycin have been reported, resulting in the prediction of future difficulties with vancomycin use. A comparison of outcomes between MRSA and methicillin-sensitive S. aureus infections suggests a higher patient mortality rate with the resistant strains (21% versus 8%) [5]. Current therapeutic options for treating MRSA infections include vancomycin, teicoplanin, quinupristin/ dalfopristin, and linezolid. Vancomycin has become the drug of choice for MRSA because of its low cost and relatively low toxicity. However, reliance solely on vancomycin for control of MRSA is suboptimal because this antibiotic requires both intravenous (IV) administration and therapeutic drug monitoring. Additionally, vancomycin treatment promotes a selective pressure on the hospital s microbial flora and does not have comparable bactericidal activity when compared with -lactam antimicrobials in the treatment of serious methicillinsensitive S. aureus infections [6 8]. The inpatient cost of treating gram-positive severe infections with IV antibiotics is significant, and there is an increasing need to provide effective treatment for these infections in the outpatient setting. Linezolid, a synthetic antimicrobial, is the first member of the oxazolidinone class that inhibits bacterial protein synthesis by preventing formation of the 70S initiation complex [9, 10]. Linezolid has in vitro and in vivo activity against a broad range of antibiotic-susceptible and resistant gram-positive bacteria and it lacks cross-resistance with current antimicrobial therapies owing to its novel mechanism of action. The 100% oral bioavailability of linezolid may allow for early switch (ES) to oral therapy for gram-positive infections [11, 12]. Several studies have demonstrated the safety and efficacy of switching patients who are clinically stable to appropriate oral antibiotics to decrease hospital length of stay (LOS) for a variety of infections [13 19]. We conducted a retrospective analysis to evaluate the potential opportunity of switching vancomycin IV therapy to oral linezolid in patients with active endocarditis and surgically treated with valve replacement. Material and Methods This study was conducted in agreement with the revised Declaration of Helsinki. The institutional review board approved the protocol, and all patients provided written informed consent. A retrospective analysis of the hospital 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 88 COLLI ET AL Ann Thorac Surg EARLY SWITCH TO ORAL LINEZOLID 2007;84:87 91 Table 1. Vancomycin Infusion Rates Estimated Creatinine Clearance Vancomycin Infusion Rate 50 ml/min 83 mg/h ml/min 63 mg/h ml/min 42 mg/h 10 ml/min 21 mg/h CVVH 42 mg/h fulfilled all other ES criteria remained eligible for continuation of linezolid therapy. Patients underwent clinical and microbiologic follow-up at 30 days, 6 months, and 1 year after intervention. All patients underwent cardiology visits, a transthoracic echocardiography, and three blood cultures at each follow-up. Results CVVH continuous venovenous hemofiltration. database was performed during February 2002 through August 2005 after the introduction of linezolid at our institution. All patients presenting with active native or prosthetic valve left-sided endocarditis caused by resistant gram-positive bacteria who underwent surgical intervention for at least one valve replacement or repair were identified. The diagnosis of endocarditis at baseline was determined with the use of the modified Duke criteria [20]. The main indications for surgery were refractory cardiac failure caused by valvular insufficiency, persistent sepsis caused by a surgically removable focus, myocardial abscess, persistent life-threatening embolization, mobile vegetations greater than 10 mm, persistent pyrexia, and leukocytosis with negative blood cultures after 7 to 10 days of appropriate antibiotic therapy in accordance to the American College of Cardiology and American Heart Association (ACC/AHA) guidelines for surgical therapy in active infective endocarditis [21]. Bacterial identification and antibiotic susceptibility were performed using standard techniques [22] following the National Committee for Clinical Laboratory Standards recommendations [23]. Patients were considered to have failed therapy if they did not respond to the study drug protocol on the basis of ongoing signs and symptoms of infection. Patients experienced microbiologic failure if their infection persisted or relapsed as denoted by ongoing positive cultures, leading to discontinuation of the study drug or subsequent isolation of bacteria of the same strain after apparent clinical improvement. All patients were treated before surgical intervention with IV vancomycin (target vancomycin blood level was between 10 and 15 mg/l) for at least 24 hours. After the intervention, patients were treated with continuous infusions of vancomycin to achieve a plateau blood concentration of 20 to 25 mg/l. The IV vancomycin protocol was as follows: loading dose was infused during the 1 hour after intensive care unit arrival after intervention. If the patient weighed less than 65 kg, 1 g of vancomycin was given; if the patient weighed more than 65 kg, 1.5 g was given. A continuous infusion of vancomycin (dilution, 10 mg/ml) at a rate dependent on the estimated creatinine clearance (Table 1) was administered. Daily serum samples were taken. The infusion rate was adjusted according to serum concentration (Table 2). If the patient fulfilled ES criteria (Table 3), oral linezolid 600 mg every 12 hours was initiated and continued for 3 weeks. Patients who had a single relapse in their clinical condition (eg, developed one episode of fever) but who otherwise During the study period, 14 patients were surgically treated for left-sided active endocarditis. There were 10 male and 4 female patients, and the mean age was years. Ten patients were admitted with New York Heart Association class III criteria, and 4 patients satisfied New York Heart Association class IV criteria. Four patients were admitted directly to the intensive care unit, and of these, 3 were already receiving mechanical ventilation. Four patients presented with renal failure (creatinine 2 mg/dl). All patients had at least one absolute indication for early surgical treatment. The most frequent indication was worsening heart failure (8 patients, 60%) and the inability to control the infection (6 patients, 40%). One patient experienced an embolic stroke 2 weeks before admission. Twelve patients (85%) presented with an active native valve endocarditis, and 2 patients (15%) presented with an active prosthetic valve endocarditis (1 early endocarditis and 1 late). Twelve patients (85%) presented preoperatively with positive blood cultures, and 2 patients (15%) had negative preoperative blood cultures. Eight patients (60%) presented with MRSA (minimum inhibitory concentration [MIC] 2 mg/l), 4 patients (30%) presented with penicillin-resistant viridans group streptococci (1 Streptococci mutans, 3 Streptococci oralis, MIC 0.5 mg/l). In the 2 patients (15%) with culture-negative endocarditis, pathogens were identified from the culture of the resected valves. In both cases, multidrug-resistant enterococci (resistant to penicillin MIC 16 mg/l, resistant to gentamicin MIC 500 mg/l, and vancomycin susceptible MIC 4 mg/l) were identified. All patients presented with at least one valve vegetation, and 1 patient presented with an intracardiac abscess. One patient (7%) was an IV drug user, and he presented with vegetations on the aortic, mitral, and tricuspid valves. Six patients (40%) presented with vegetations on the aortic valve, 6 patients (40%) on the mitral valve, and 1 (7%) on both the aortic and mitral valves. The 2 patients with prosthetic valve endocarditis (1 mitral and 1 aortic) presented with prosthesis dehiscence. Patients were operated on 3 to 10 days (mean, days) after confirmation of a diagnosis of endocarditis. Table 2. Infusion Rate Adjustments According to Vancomycin Blood Concentration Vancomycin Blood Concentration Infusion Rate Adjustment 15 mg/l 21 mg/h mg/l No changes 25 mg/l 21 mg/h 30 mg/l Stop for 6 h

3 Ann Thorac Surg COLLI ET AL 2007;84:87 91 EARLY SWITCH TO ORAL LINEZOLID Table 3. Criteria for Early Switch a Afebrile Ability to take oral medications Clinical improvement No non gram-positive infections requiring intravenous antimicrobials Normal or normalizing white blood count (WBC) No linezolid contraindications No temperature 37.8 C for 24 consecutive hours Fulfilment of one of the following: Oral diet or feeds through a nasogastric or gastric feeding tube Taking oral medications All infections: No evidence of hypotension or shock, clinician-documented impression of clinical improvement Pneumonia: At baseline O 2 requirements, Pao 2 /Fio 2 200, stable or improved pulmonary infiltrates, improvement in cough, sputum production, hemoptysis if present Skin and soft tissue infection: Cessation of purulent drainage from a wound if present, improved edema, induration, or erythema of the cellulitic area or wound Urinary tract infection: Improved dysuria, suprapubic pain, costovertebral angle tenderness, decreased pyuria Catheter infection: Resolution of purulent drainage from the catheter site, improved erythema or induration of the catheter site, resolution of bacteremia if repeat cultures were performed Primary bacteremia: Resolution of fever, chills, rigors, resolution of bacteremia with repeat cultures if performed Abscess: Adequate drainage with intravenous antimicrobials, radiographic or clinical improvement of the infection No resistant gram-negative infections requiring carbapenems, intravenous cephalosporins, aminoglycosides No fungal infections requiring amphotericin B or intravenous triazoles Normal: 11,000 WBC/ L Normalizing: Three consecutive decreasing WBCs on 3 separate days with the final value 12,000 WBC/ L No hypersensitivity to linezolid Absolute neutrophil count 1,000/ L Total WBC 1,500/ L Hematocrit 20% Platelets 75,000/ L 89 a Modified from Parodi and colleagues [19]. All operations were performed using standard methods of cardiopulmonary bypass. Myocardial protection was achieved using antegrade warm blood cardioplegia in 8 patients (60%) and antegrade crystalloid cardioplegia (Custodiol; Koehler Chemie, Alsbach-Haenlein, Germany) in 6 patients (40%). Mechanical prosthetic valves (Bicarbon Sorin) were used to replace native valves in four (30%) patients (three mitral valve replacement and one double valve replacement). Bioprosthetic valves were used in 10 (70%) patients (4 Carpentier-Edwards, 4 Epic St. Jude Medical, 2 Björk-Shiley [Sheligh Inc, Millburn, NJ]); 4 aortic valve replacements, 5 mitral valve replacements, and 1 double-valve replacement). In one case of tricuspid valve endocarditis, vegetation removal and partial resection of the cusp, along with a De Vega annuloplasty, was performed. The mean intensive care unit LOS was days. The total hospital LOS was days. Early switch to oral linezolid occurred after days from the surgical intervention Four (30%) patients were discharged directly home, and 10 (70%) patients were transferred to a rehabilitation center. Clinical follow-up was performed at 30 days, 6 months, and 1 year after intervention. Follow-up was completed in 100% of the study patients. All the blood cultures performed at follow-up were negative. No operative deaths within 30 days of the procedure occurred. There were 2 late deaths, resulting in an overall late mortality of 14.3%. Both patients died of noncardiac causes. One patient died of disseminated intravascular coagulation after gynecologic intervention 11 months after the mitral valve replacement with a mechanical valve. The second patient died of hemorrhagic stroke 18 months after the double-valve replacement with mechanical prostheses. Both patients were in the native valve endocarditis group. There were no cases of recurrent endocarditis during the follow-up period (mean, months; range, 12 to 36 months). With regard to morbidity, there were no cases of periprosthetic leakage. One patient (7%) experienced early acute renal failure and underwent short-term dialysis with complete recovery. Three patients (21%) required mechanical ventilation for 48 to 96 hours postoperatively. All patients underwent safety laboratory evaluations every week for the first 4 weeks of therapy. There were no cases of drug-related complications. Comment Surgical treatment of active infective endocarditis by valve replacement or repair still remains a challenge to physicians because it requires a surgically demanding operation and special emphasis on the eradication of the infectious focus to prevent early postoperative prosthesis colonization. This goal can be achieved by combining aggressive debridement of infective tissue and appropriate postoperative antibiotic treatment.

4 90 COLLI ET AL Ann Thorac Surg EARLY SWITCH TO ORAL LINEZOLID 2007;84:87 91 Table 4. Cost Assumptions for the University Hospital of Parma Facility During Year 2005 Hospital Bed Costs Cost per Day Rehabilitation unit 224 Cardiology unit 321 ICU care 1141 Antibiotics average wholesale prices Generic vancomycin IV 10 Linezolid IV/PO 120 ICU intensive care unit; IV intravenous; PO per os (by mouth). The prevalence of antibiotic resistance is increasing in many countries [24]. Particularly alarming is the emergence of gram-positive organisms resistant to glycopeptides, which were traditionally considered the ultimate defense against gram-positive infections. However, the narrow therapeutic index for vancomycin limits its use as an option to boost plasma concentrations by increasing dosage without incurring increased toxicity. In addition, vancomycin cannot be given orally because of poor systemic absorption. Teicoplanin also raises concerns about toxicity, requires monitoring of levels during parenteral administration, and has been associated with longer LOS than linezolid [25]. Other antibiotics such as aminoglycosides, tetracyclines, third-generation cephalosporins, and fluoroquinolones have some activity against community-acquired MRSA strains [26] but are not sufficient for clinical use on all MRSA infections [27]. Despite good results published recently from several institutions [28 37], significant mortality and serious morbidity may be expected. Major improvements in myocardial protection and surgical reconstructive techniques, including aortic homograft implantation [38], have made surgical treatment an attractive and only option [39] in the majority of complicated cases. Predictors of long-term survival in previous studies were reported to be cardiac failure, renal impairment, prosthetic valve endocarditis [34], preoperative New York Heart Association class IV, renal failure, mitral valve endocarditis [35], advanced age, staphylococcus infection, and anular abscess [36]. The differences in survival and risk factors in these reports are likely to reflect differences in the clinical and pathologic makeup of the patients involved, and comparisons should, therefore, be cautiously undertaken. During the last 3 years, in this limited group of patients, we obtained interesting early and long-term results. Our institution accepted a policy of early surgical treatment for active-phase endocarditis in patients who developed a complication or were resistant to antibiotic treatment in accordance with the ACC/AHA guidelines [21]. In our study, we had no operative deaths, and the only two cases of late death were not cardiac-related. Operative findings (only one case of perianular abscess) also are illustrative of our policy to indicate surgical treatment as soon as it becomes evident that antibiotic treatment is inadequate or as soon as we encounter complications. Moreover, the rather small number of serious postoperative complications and the absence of recurrence of endocarditis are encouraging and suggest that combining early surgical treatment with the ES antibiotic protocol (IV vancomycin to oral linezolid) in patients with resistant gram-positive endocarditis can be considered effective and safe. The ES to oral linezolid has already been demonstrated to effectively reduce vancomycin use, hospital LOS, and economic costs in MRSA infections with exceptions for endocarditis and osteomyelitis [18, 19]. All microorganisms identified in our series were vancomycin and linezolid susceptible. We believe that the application of linezolid ES in patients surgically treated for heart valve endocarditis attributable to resistant gram-positive endocarditis could provide several advantages: avoidance of a prolonged hospital confinement and subsequent morbidity, potential economic savings by reducing the total LOS, improvements in patient satisfaction, removal of IV catheters, and reduction of the risk of acquiring new nosocomial infections. The earlier discharge periods associated with the use of a linezolid ES protocol would also diminish the reservoir of resistant gram-positive infected patients from the hospital population. This outcome is desirable for several reasons. First, the number of MRSA transmission opportunities for noncolonized patients or health-care professionals is reduced [40]. Second, the concomitant decline in vancomycin use would decrease selective pressure for resistant organisms such as vancomycin-resistant enterococci. Third, fewer hospitalized resistant gram-positive infected patients would free otherwise-committed human and financial resources for extreme infection control measures such as surveillance, contact isolation, personnel education, and improved antimicrobial utilization programs [22]. The potential economic impact of ES protocol to oral linezolid therapy is shown by the hospital bed costs and drug acquisition costs presented in Table 4. Hospital costs were obtained from the Administration and Financial Department of the University Hospital of Parma and are based on the Regional Public Health System Reimbursement criteria. In our series, the combination of surgical treatment of involved heart valves and application of the linezolid ES protocol resulted in eradication of pathogens in all patients. We also have to consider the fact that no patient presented at the time of ES with a pathogen resistant to linezolid. No patient developed drug resistance while receiving linezolid therapy. Linezolid was well tolerated, and we failed to observe any cases of clinical or laboratory adverse events related to drug therapy. Our study showed that the combination of an aggressive surgical intervention and a linezolid ES protocol for resistant gram-positive heart valve endocarditis is an effective treatment and offers the potential for decreased vancomycin utilization, decreased LOS, and health-care cost savings. The absence of hospital mortality, cardiac long-term mortality, recurrence of infection, and need for reintervention was encouraging. The interesting results we observed are limited to this select group of patients. Owing to the limitations of our study (small sample size, retrospective analysis, single

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