Ann Thorac Surg 2007;83:1888-1891
© 2007 The Society of Thoracic Surgeons
Case Reports
Methicillin-Resistant Staphylococcus Aureus Pneumonia After Thoracic Surgery: Successful Treatment With Linezolid After Failed Vancomycin Therapy
Daniel Salerno, MD,
Bobbak Vahid, MD*,
Paul E. Marik, MD, FCCM
Department of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
Accepted for publication November 20, 2006.
* Address correspondence to Dr Vahid, Thomas Jefferson University Hospital, 834 Walnut St, Suite 650, Philadelphia, PA 19107 (Email: bobbak.vahid{at}mail.tju.edu).
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Abstract
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We describe 3 patients with methicillin-resistant Staphylococcus aureus, hospital-acquired pneumonia who demonstrated a microbiological and clinical failure with vancomycin despite adequate trough levels. All 3 patients were cured with linezolid.
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Introduction
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Epidemiological data have shown that pneumonia is the most common nosocomial infection in intensive care units both in the United States and Europe [1]. The crude mortality of hospital-acquired pneumonia (HAP) is estimated at 31% with an odds ratio for death of 1.9. Hospital-acquired pneumonia increases hospital length stay by 4 to 13 days. The cost of treatment for each episode of HAP is more than $40,000 [2]. Hospital-acquired pneumonia clearly represents a serious complication for hospitalized patients and a significant burden for the health care system. Gram positive bacteria are being increasingly recognized as a cause of nosocomial infections. Staphylococcus aureus has been reported in 17% to 30% of HAP [1]. More specifically, methicillin-resistant S. aureus (MRSA) accounts for 60% of all the S. aureus isolates. Therefore, antimicrobial agents with activity against MRSA have become an integral part of the antibiotic armamentarium in patients with suspected HAP. The American Thoracic Society HAP guidelines recommend the use of vancomycin when MRSA is considered a causing agent [3]. Nevertheless the same guidelines caution about the high clinical failure rates of vancomycin when it is given in the standard dose (1 g intravenously every 12 hours). Linezolid has been proposed as an alternative to vancomycin for the coverage of MRSA in HAP, especially in patients with renal failure in whom vancomycin is frequently under dosed [3]. Linezolid has been shown to be equivalent to vancomycin in treatment of S. aureus bacteremia, febrile neutropenic patients, and complicated skin and soft tissue infections [4, 5]. Studies have also demonstrated that linezolid is cost-effective or cost-neutral in comparison with vancomycin in treating HAP [6]. However, the use of linezolid as a first-line agent for MRSA pneumonia is still controversial. We describe 3 cases of MRSA pneumonia with microbiologically proven vancomycin failure who demonstrated a microbiological and clinical cure after switching treatment to linezolid.
We describe 3 cases of MRSA-HAP after thoracic surgery. Table 1
summarizes these cases. Pneumonia was diagnosed in each case based on fever, respiratory failure, new pulmonary infiltrates on chest roentgenogram, and increased sputum production. The patients required intubation and mechanical ventilation for progressive respiratory failure. Lung protective strategies were used whenever the patients met the criteria of adult respiratory distress syndrome. Enteral feeding was started within 24 hours after intubation.
Bronchoscopy with bronchoalveolar lavage (BAL) and quantitative culture was done on each patient to establish a microbiologic diagnosis. A threshold of greater than 10,000 colony forming unit/mL was used to diagnose pneumonia. Chest roentgenogram was used to guide bronchoscopy. The BAL was obtained from the most involved lobe on the chest roentgenogram. Three aliquots (60 mL sterile 0.9% NaCl solution) were used as the instillate. The recovered lavage fluids were pooled into a single container (non-cell adherent plastic) and were sent to the microbiology laboratory for quantitative cultures. The initial antibiotic regimen included vancomycin (15 mg/kg) intravenously every 12 hours and piperacillin/tazobactam (3.375 gm intravenously every 6 hours). The bronchoscopy was done 2 to 6 hours after the first dose of antibiotics in all cases. The piperacillin/tazobactam antibiotic was discontinued when the culture results revealed MRSA. The vancomycin serum trough level was measured after the third dose. A clinical pharmacist was available to adjust the dose of vancomycin to trough levels 15 to 20 µg/mL. The mean vancomycin levels are shown in Table 1. Arterial blood gas and white blood cell counts were measured daily.
All 3 patients remained intubated with persistent fever. The bronchoscopy was repeated 5 to 7 days after vancomycin therapy. High-MRSA colony counts were considered treatment failure. Treatment was changed to linezolid. The bronchoscopy was repeated 5 to 7 days after the initial dose of linezolid.
Initial quantitative cultures of BAL specimens grew high colony counts of MRSA (50,000 to 100,000 cfu/mL). The trend of BAL colony counts after vancomycin and linezolid therapy is shown in Figure 1. The BAL colony count remained high after 5 to 7 days of vancomycin therapy in each case despite adequate trough levels. The BAL colony count dramatically declined after treatment with linezolid. Improvements in oxygenation in all patients were noted after treatment with linezolid. The chest roentgenograms showed persistence of the pulmonary infiltrates on vancomycin therapy in all 3 cases. The pulmonary infiltrates improved after 7 days of linezolid therapy. All 3 patients were successfully liberated from the ventilator after 3 to 5 days after linezolid therapy.
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Fig 1. Quantitative culture of bronchoalveolar lavage (mean cfu/mL) (A) at the time of diagnosis, (B) after 5 to 7 days of vancomycin therapy, and (C) after 5 to 7 days linezolid therapy.
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Comment
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Although both vancomycin and linezolid have activity against MRSA, their intrapulmonary pharmacokinetics are considerably different. Lamer and colleagues [7] studied 14 ventilated, critically ill patients and calculated the concentration of vancomycin in the epithelial lining fluid. Using albumin concentration in the epithelial lining fluid as a surrogate marker of lung inflammation they concluded that the alveolar concentration of vancomycin was 24.6% of the plasma concentration in the inflamed lungs and 14% in the normal lungs. The minimal inhibitory concentration (MIC) of vancomycin against S. aureus is between 0.25 to 2 mcg/mL. These investigators suggested that a trough plasma level of at least 20 mcg/mL was necessary to achieve alveolar levels of vancomycin above minimal inhibitory concentration for S. aureus. Levels greater than 20 mcg/mL are rarely used in clinical practice because of concerns about toxicity. In a study of healthy subjects, Conte and colleagues [8] administered the standard dose of linezolid until achieving a steady state; the concentrations of linezolid in the epithelial lining fluid were much greater than the minimal inhibitory concentration for MRSA.
In 2001, a randomized double-blind study was reported that compared linezolid with vancomycin for the treatment of HAP [9]. This study was designed as an equivalence and safety study. One-hundred and forty-two patients were enrolled in the linezolid arm and 131 in the vancomycin group. Both groups received aztreonam for gram-negative bacterial coverage. There was no significant difference in clinical, radiographic, or microbiological outcome between the two groups. A follow-up study with similar design was reported in 2003. Two hundred nine patients were treated with linezolid and 187 patients were treated with vancomycin. This study also showed no difference in outcome [10]. A subsequent analysis of data from these two studies showed that in the subset of patients with proven MRSA pneumonia, the survival was statistically higher in the linezolid group as compared with the vancomycin group (85% and 67%, respectively; p = 0.05) [11]. The authors suggested that the poor penetration of vancomycin into the lungs could play a role in the observed outcomes.
The United States Centers for Disease Control and Prevention (CDC) report that the mean incidence of ventilator-acquired pneumonia in medical intensive care units and trauma units are 7.4 and 16.3 cases per 1,000 ventilator days, respectively. The rate of ventilator-acquired pneumonia in our intensive care unit is 5.91 cases per 1,000 ventilator days that is slightly lower than mean incidence reported by the CDC. In 2006 there were five cases of MRSA pneumonia (including the reported cases) that were diagnosed in our intensive care unit. The other 2 patients were treated with vancomycin. One patient died secondary to massive pulmonary embolism and the other patient died due to cardiogenic shock. Overall, S. aureus has been isolated from 17% to 30% patients with HAP [1]. Because MRSA accounts for more than 50% of all the S. aureus isolates in the United States, MRSA pneumonia in intensive care units is a common and serious problem.
Although our patients were treated with appropriate doses of vancomycin, they failed to show a microbiologic response. All 3 patients demonstrated a microbiologic cure after linezolid therapy. These observed differences may be explained by better penetration of linezolid into lung parenchyma as compared with vancomycin. There are no clear guidelines to help clinicians decide between vancomycin and linezolid for the treatment of MRSA pneumonia. Our experience suggests that linezolid may be the drug of choice for proven MRSA pneumonia. Alternatively, if vancomycin is used as a first-line therapy, the drug should be dosed to achieve adequate trough levels, and treatment should be switched to linezolid if the patient’s condition fails to improve within a few days. Follow-up quantitative cultures should be considered in patients with MRSA pneumonia treated with vancomycin to diagnose early microbiological failure. At this time the optimal antibiotic therapy for MRSA-HAP remains unclear, and prospective randomized trials are required to answer this important question.
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References
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- Richards MJ, Edwards JR, Culver DH, et al. Nosocomial infections in combined medical-surgical intensive care units in the United States Infect Control Hosp Epidemiol 2000;21:510-515.[Medline]
- Boyce JM, Potter-Bynoe G, Dziobek, et al. Nosocomial pneumonia in Medicare patients: hospital costs and reimbursement patterns under the prospective payment system Arch Intern Med 1991;151:1109-1114.[Abstract]
- American Thoracic Society Infectious Diseases Society of AmericaGuidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388-416.[Free Full Text]
- Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus bacteraemia: pooled analysis of randomized studies J Antimicrob Chemother 2005;56:923-929.[Abstract/Free Full Text]
- Jaksic B, Martinelli G, Perez-Oteyza J, et al. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer Clin Infect Dis 2006;42:597-607.[Medline]
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- Lamer C, de Beco V, Soler P, et al. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients Antimicrob Agents Chemother 1993;37:281-286.[Abstract/Free Full Text]
- Conte Jr JE, Golden JA, Kipps J, Zurlinden E. Intrapulmonary pharmacokinetics of Linezolid Antimicrob Agents Chemother 2002;46:1475-1480.[Abstract/Free Full Text]
- Rubinstein E, Cammarata S, Oliphant T, et al. Linezolid Nosocomial Pneumonia Study Group Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study Clin Infect Dis 2001;32:402-412.[Medline]
- Wunderink RG, Cammarata SK, Oliphant TH, et al. Linezolid Nosocomial Pneumonia Study Group Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia Clin Ther 2003;25:980-992.[Medline]
- Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs. vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia Chest 2003;124:1789-1797.[Medline]
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Abstract
Introduction
