S t a p h y l o c o c c u s au r e u s B a c t e re m i a , R i s k F a c t o r s , Complications, and Management

Yoav Keynan,
KEYWORDS  Staphylococcus aureus  Infection  MSSA  MRSA  Treatment  Antibiotics  Vancomycin  Linezolid  VAP  HAP KEY POINTS
 Staphylococcus aureus and methicillin-resistant S aureus have emerged as the most important nosocomial pathogens.  Traditional therapy may be sufficient in most but not all patients, in whom alternatives should be sought.  The infection is often complicated with several sites of metastatic foci and is nosocomial frequently.  New antibiotics to fight MRSA have been introduced and are equivalent or better than vancomycin.
MD,

Ethan Rubinstein,

MD, LLB*

INTRODUCTION

Staphylococcus aureus (SA) is a leading cause of community-acquired and hospitalacquired bacteremia. S aureus bacteremia (SAB) can lead to seeding of virtually any body site and ensuing complications. These complications may result in severe disease, resulting in significant morbidity and death. Complications of SAB are common, occurring at rates that range from 11% to 53%.1,2 Some complications more frequently require intensive care admission and carry poor prognosis because of the anatomic site or the difficulty in reaching a timely diagnosis. The risk factors that predispose to developing dissemination and seeding as a consequence of SAB bacteremia depend on the route of acquisition, site of infection, presence or absence of foreign material, pathogen characteristics, and host predisposition. Community acquisition is associated with a propensity for metastatic complications.3,4 Lautenschlager and colleagues4 reported a twofold higher rate of metastatic

Section of Infectious Diseases, Department of Internal Medicine and Medical Microbiology, University of Manitoba, 543-745 Bannatyne Ave, Basic Sciences Bldg, Manitoba R3E 0J9, Canada * Corresponding author. E-mail address: rubinste@cc.umanitoba.ca Crit Care Clin 29 (2013) 547562 http://dx.doi.org/10.1016/j.ccc.2013.03.008 criticalcare.theclinics.com 0749-0704/13/$ see front matter 2013 Elsevier Inc. All rights reserved.

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seeding in community-associated (CA-SAB) versus hospital-associated SAB (HA-SAB). Fowler and colleagues5 went on to identify some of the predictors for occurrence of complication in a prospective cohort study. The most robust predictor was a persistent positive blood culture at 48 to 96 hours, and the combination of 4 clinical parameters: community acquisition, skin findings suggesting acute systemic infection, persistent fever at 72 hours, and positive follow-up blood cultures at 48 to 96 hours were useful for predicting complicated SAB. The reasons behind the high rates of complications in patients with community-onset infection may be related to the longer time until bacteremia is identified and possibly the presence of the Panton-Valentine Leucocidin (PVL) present in community-originating SA strains (CA-MRSA). Supporting the first notion is a prospective study that correlated the presence of complications among 245 cases of SAB with duration of bacteremia. There was a linear association with rates of 6.6% in bacteremia of fewer than 2 days duration up to 38% in those with bacteremia of more than 4 days duration.6 The absence of an obvious source of bacteremia has been shown to serve an important predictor of subsequent complications. In a series of 281 patients with SAB, the incidence of a metastatic complication was 2.5-fold lower with an identifiable source of bacteremia than among patients without an apparent source.3,7 The presence of prosthetic devices is frequently implicated as the source for SAB, as well as being an important risk factor for the development of complicated course, with mortality rates of up to 18% and a relapse rate of 15%.8 Higher rates of complications are seen among immunosuppressed patients. Among patients with HIV, both the underlying immunocompromised state, the behavioral risk factors associated with HIV acquisition, and treatments may all contribute to an increased risk of complications. In a study from before the high-intensity antiretroviral therapy (HAART) era, the incidence of SAB among a large population of HIV-infected patients was 5.4 episodes per 1000 patients.9 More than one-third of these patients developed metastatic sequelae. A more contemporary study included 131 episodes of SAB, two-thirds caused by MRSA, of which more than half were attributed to CA-MRSA. Nearly half developed endocarditis and the mortality rate was 8%. CA-MRSA was associated with endocarditis and mortality, but other comorbid conditions, current receipt of antiretroviral therapy, preculture severity of illness, or CD4 count were not predictive of either endocarditis or in-hospital mortality.10 Individuals with SAB in the setting of underlying malignancy also have high rates of complications, ranging from 30% to 40% in some reports.11,12 The presence of renal failure (odds ratio [OR] >12) and an underlying solid tumor predict intravascular complications.11 Microbial factors, such as the previously mentioned PVL, the presence of hemolysin, pathogenic elements, antibiotic susceptibility, and so forth all contribute singly or collectively to more severe courses, organ invasion (particularly soft tissue and the lung), and to a disease course that is more complicated, difficult to treat, and subsequently leading to a higher mortality.
CORRELATES OF DISEASE SEVERITY AND COMPLICATIONS

The rapidity with which blood cultures become positive from the time of obtaining the blood culture has been correlated with the presence of complications (Table 1). Growth of SA within 14 hours after blood culture was associated with a higher complication rate in a prospective observational study of 312 cases of SAB. Khatib and colleagues13 performed a logistic regression analysis and were able to demonstrate that a shorter time to the blood culture turning positive was an independent predictor of an endovascular source of infection, extended bacteremia, metastatic infection, and

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Table 1 Factors associated with increased severity of SAB Factor Community acquired Female sex Length of positive blood cultures >48 h Time for a blood culture to turn positive Lack of identifiable focus Implanted prosthetic material Immunosuppression and HIV Renal failure Solid tumors High APACHE II score (>7) CURB-65 >3 Neurologic complications Cardiac complications Septic thrombophlebitis MRSA pneumonia Impact on SAB Tendency for metastatic infection Higher mortality rate (than males) Complicated course (including metastatic infections) Complicated course (including metastatic infections and mortality) Aggravates and prolongs SAB Complicated course, increased mortality, increased relapse Aggravates and prolongs SAB Intravascular complications Intravascular complications Complicated course, septic shock, high mortality Complicated course, septic shock, high mortality High mortality High mortality Prolonged course Complicated course, septic shock, high mortality References
14 17 5

13

3,7 8,20,21

9,10 11,12 11,12 14 16 18,29 19 30,31 32

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CURB-65, confusion, urea, respiratory rate, blood pressure, and age 65; MRSA, methicillin-resistant Staphylococcus aureus; SAB, Staphylococcus aureus bacteremia.

attributable mortality. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has also been investigated as a potential tool for prediction of SAB complications. Yzerman and colleagues14 evaluated the utility of APACHE II scores in predicting the risk of metastatic foci or death among 99 prospectively identified patients with SAB. Eleven presented with shock and, of those, 10 (w90%) died. The rate of complications and mortality both increased with higher APACHE scores (mortality rate of 44% in the 79 score; 88% among those with APACHE II >10). A change in APACHE score of 7 or more had a positive predictive value of 53% and 83%, respectively, for fatal and complicated outcomes. A second series published in the same year found similar association between the APACHE score and subsequent mortality.15 In a study of 241 patients diagnosed with SAB, 135 caused by methicillin-resistant and 106 with methicillin-susceptible isolates, the predictive capacity of Rapid Emergency Medicine Score (REMS) and the CURB-65 (confusion, urea, respiratory rate, blood pressure, and age 65) were assessed. Both scores were found to be useful in predicting outcomes. CURB-65 score higher than 3 or REMS higher than 6 at the first evidence of SAB correlated with attributable mortality rates of 34.9% and 26.5%, respectively.16 An interesting cohort study of SAB included retrospective assessment of 1093 patients. The 30-day all-cause mortality was 39.3%. Higher rates of septic shock were seen among women and the mortality rate for women was 44.8% compared with 35.4% in men. Female sex remained an independent risk factor for 30-day mortality in a logistic regression analysis, with OR of 1.54.17

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SYSTEMIC AND FOCAL END ORGAN COMPLICATIONS

Virtually any tissue, organ, or foreign material can become the focus of dissemination and seeding during SAB. Several complications are worth mentioning. Infective endocarditis (IE) is a frequent complication of SAB and carries a risk for severe sepsis, neurologic complications, and high mortality rates. A prospective study comparing SA with other microbial causes of IE demonstrated the incidence of neurologic complications is greater than 2 in cases caused by SA and mortality was 34%, 3 times higher than the non-SA.18 These rates are even higher when a prosthetic valve is involved. A study by John and colleagues19 documented cardiac complications in two-thirds of patients with SA PVE, and central nervous system (CNS) complications were detected in a third. The presence of cardiac complications was strongly associated with in-hospital mortality. Other prosthetic devices are also important sites of SA seeding and permanent pacemakers and cardioverters-defibrillators, with more than half of such devices becoming involved during SAB bacteremia.20 The incidence of seeding of cardiac-assist devices during SAB remains to be determined. Orthopedic prostheses are also at high risk of seeding during SAB bacteremia with rates of up to 34% reported.21 Metastatic infection of native tissue can occur in patients with SAB with up to a third of patients who develop at least one metastatic infection.22 Although such metastatic sites of infection can appear early in the course of the infection, it is important to recognize that some metastatic seeding may not become clinically evident for several weeks, especially in the critically ill patient who is unable to localize symptoms. One such site of hematogenous spread of SAB is the vertebral column. Two studies from the same group of investigators from Denmark showed high rates of vertebral involvement, especially among patients older than 50 and the incidence increased in the latter period of the infection.23,24 They also showed that the incidence of vertebral involvement was higher in community-acquired cases, supporting the notion that longer duration of bacteremia leads to higher rates of seeding. In addition, involvement of extra-axial joints is not uncommon, due to the privileged vascular supply to synovial tissue, and this complication is reported in up to 10% of cases in some series.4 The most common joint involved is the knee. Immunosuppression or preexisting rheumatic condition or previous joint damage provide a predilection for joint involvement during SAB.25,26 Seeding of the CNS may occur as a complication of SAB. Although more commonly the result of intracranial surgery, in 2 series of patients with SA meningitis, between 27% and 34% of patients developed meningitis as a consequence of SAB.27,28 A more recent series from the United States included 33 cases with SA meningitis, of which 36% were postoperative and 64% represented hematogenous meningitis. MRSA isolates accounted for nearly a half of the cases, and CA-MRSA type USA 300 represented 56% of all MRSA isolates.29 Septic thrombophlebitis due to SA is usually an iatrogenic complication caused by an infected intravascular catheter or another device. Patients with intravascular nidus of infection tend to have prolonged or persistent fever and recurrent or continuous episodes of bacteremia. The local clinical evidence of infection at the catheter site, or signs of venous compromise (distal edema) may be lacking. Cases of Lemierre syndrome, presenting with neck, facial deep-seated infection, and bacteremia, accompanied by septic pulmonary emboli has been reported in the setting of both methicillin-sensitive SA (MSSA) and MRSA infections and in some of the cases, PVL was demonstrated.30,31 Pulmonary complications of SAB occur more frequently among injection drug users, who develop septic emboli to the lungs associated with tricuspid valve vegetation. Patients often present with fever, pleuritic chest pain, and sometimes hemoptysis.

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The presence of multiple nodular infiltrates should dictate directed history and diagnostic testing. In patients with CA-MRSA infections complicating a preceding viral infection, severe MRSA pneumonia also may develop, causing bacteremia, lung abscesses, empyema, leucopenia, and death.32
PATHOGENESIS

The vascular endothelium serves as a barrier between the bloodstream and the tissues, preventing bacterial tissue invasion. During SAB, both proinflammatory mediators and pathogen-induced endothelial injury impairs the vessel integrity, thereby leading to tissue invasion. Dysfunctional endothelium plays a role in generation of the systemic inflammatory response and initiation of small-vessel thrombosis, with ensuing activation of the coagulation cascade. The combination of inflammation, disrupted blood flow, and dysfunctional endothelium mediate a decrease in tissue oxygenation. A major culprit in SA-associated endothelial dysfunction is the staphylococcal a-hemolysin (SAHa), a pore-forming cytotoxin ubiquitously secreted by most strains of SA, which directly contributes to endothelial injury.33,34 The A-disintegrin and metalloprotease 10 (ADAM10) has been recently identified as the receptor for SAHa. It is widely expressed on the endothelium and regulates cellular adhesion and migration.35 ADAM10 mediates proteolytic cleavage of the extracellular domain of vascular endothelial cadherin and disrupts its intercellular interactions,36 leading to increased endothelial permeability. Powers and colleagues37 examined the role of ADAM10 in toxin-mediated endothelial barrier disruption. Using a mouse model, they not only illustrated this effect, but were also able to restore vascular integrity using an ADAM10 inhibitor. SAB is also influenced by the ability of SA to activate coagulation through a myriad of interactions mediated by multiple bacterial proteins. Among those are protein A, fibronectin A and B (FnBPA and FnBPB), and clumping factor A and B (ClfA and ClfB), sharing structural homology and binding affinities and mediating an interaction with extracellular matrix molecules, such as fibrinogen, vitronectin, laminin, and elastin.3840 The fibronectin-binding proteins A and B (FnBPA and FnBPB) are also capable of activating platelets through the interaction between fibronectin and fibrinogen with a low-affinity GpIIbIIIa receptor. It is thought that prior exposure (either infection or colonization) leads to antibody formation against FnBPA and B and that the antibodies may be able to bind to staphylococci and to platelets through the FcgRIIa protein. This interaction leads to platelet activation with ensuing platelet adhesion, platelet degranulation, aggregation, and thrombus formation.41 Another interaction is mediated by protein A. This surface adhesin is able to bind to the Fc fragment of antibodies, von Willebrand factor (vWF), tumor necrosis factor receptor-1, and platelets. In addition, it has been shown that protein A mediates a vWF-GP1b interaction, thereby initiating thrombus formation.42,43 Many studies have documented the role of staphylococcal surface adhesins in interacting with multiple pathways culminating in thrombus formation, directly through coagulation factors or through interaction with the vascular endothelium. It has been suggested that more virulent strains possess greater ability to mediate these endothelial and coagulation interactions. These may serve as potential targets for future therapeutics.44,45
MANAGEMENT OF SA COMPARING THE PRE-ANTIBIOTIC ERA IN BACTEREMIA

As mentioned earlier, patients with SAB can develop diverse complications (eg, IE, vertebral osteomyelitis, epidural abscess, discitis), which may be difficult to recognize and which can lead to disability and to death. The management of such patients has been proven to benefit from the involvement of infectious diseases experts. Similarly,

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when cardiac complications or spinal involvement arise, the involvement of cardiologists, cardiac surgeons, and spinal surgeons is helpful.4648 Before the introduction of effective antibiotics, the mortality from SAB was approximately 80%.49 Recent series have still shown a mortality rate of 20% to 40%. Comparing the pre-antibiotic era to the era of effective antistaphylococcal antibiotics for HA-SAB, crude 30-day mortality decreased from 27.8% to 21.8% (a 22% reduction), whereas the change for CA-SAB was smaller (26.5%25.8%). By multivariate Cox regression, age, female sex, time period, functional score, and alcohol-related diagnoses were associated with increased mortality in a European series, regardless of the mode of acquisition.50 In Australian aboriginals, similarly, the incidence of CA-SAB increased while mortality (due to young age) decreased.51 In the United States, a similar picture prevails.52 The guidelines of the Infectious Diseases Society of America recommend echocardiography for every case of SAB, particularly for CA-SAB, in which an echocardiogram is essential,53 as the frequency of endocarditis in CA-SAB is high (w30%).54 The transesophageal echocardiogram (TEE) provides more information than the transthoracic echocardiogram (TTE) and is the preferred diagnostic modality.5558 Exceptions are patients who are young and previously healthy who have no underlying cardiac predisposing conditions or clinical signs of endocarditis, and whose fever and bacteremia resolve within 72 hours following removal of a likely focus (such as intravascular catheter). The best results of TEE/TTE are obtained if the procedure is performed 5 to 7 days following the onset of CA-SAB and in Hospital acquired S.aureus bacteremia (HA-SAB) lasting longer than 4 days. The presence of a permanent intracardiac device, hemodialysis dependency, spinal infection, or nonvertebral osteomyelitis have a high association with endocarditis, making TEE in these high-risk patients mandatory.59
Empiric Antibiotic Therapy

Empiric therapy depends on the local epidemiologic data, particularly for HA-SAB. An increased incidence rate of MRSA and potential prevalence of SA strains with high vancomycin minimal inhibitory concentration (MIC) make susceptibility testing to guide antibiotic therapy essential. In the absence of controlled clinical trials that specifically address this issue, we recommend a combination of anti-MSSA agent (eg, flucloxacillin, methicillin, oxacillin, cefazolin, cefuroxime, ceftriaxone), and vancomycin should be administered pending susceptibility results. The reason for this recommendation is the superior activity of beta-lactams compared with vancomycin for MSSA6062 combined with the fact that these antibiotics do not cover MRSA. In a new publication describing in vitro experiments, the combination of nafcillin and vancomycin significantly improved antibacterial activity against hVISA (vancomycin intermediate susceptible S.aureus [VISA] with heteroresistance pattern to vancomycin), MRSA, and MSSA compared with either drug alone.63 Furthermore, no antagonism between these 2 agents is known for any pathogen. The recommended dose of vancomycin is a loading dose of 30 mg/kg in severe cases followed by 15 mg/kg per day every 12 hours with attention paid to weight and renal function and with the vancomycin dose not to exceed 2 g per day unless levels are measured routinely.64 Serum trough concentrations should be monitored and the dose adjusted to obtain trough levels of approximately 12 to 17 mg/mL. Of note is that some patients in the intensive care unit may have higher volume of distribution of vancomycin and accelerated clearance, particularly in the phase of fluid resuscitation, thus resulting in 33% lower than recommended vancomycin in the area under the time concentration curve.65 It is hoped that in the not too distant future, nonculture-based microbiologic-diagnostic methods, such as matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry and DNA detectionbased methods will allow for a more rapid

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identification of SA and rapid determination of whether it is MSSA or MRSA through the detection of the mecA gene. When susceptibilities of SA become known, a more focused therapy becomes feasible. If the organism is MSSA, nafcillin, oxacillin, or flucloxacillin are the agents of choice. Some centers use first-generation and second-generation cephalosporins, such as cefazolin and cefuroxime or cefamandole as their first choice; clinical studies have shown that the anti-staphylococcal activity of all these agents is similar.66 There is little difference between the various cephalosporins of the first and second generation with regard to clinical effects in MSSA bacteremia.67 As discussed previously, vancomycin should not be used for MSSA infections because of its inferior clinical results in systemic MSSA infections, including MSSA SAB.68,69 In addition, the relapse rate of MSSA when treated with vancomycin is far higher than when treated with betalactams (odds ratio 4.1; confidence interval 1.511.6).70 Further, a fraction of MSSA show increased vancomycin MIC contributing to the decreased success rate of vancomycin in MSSA infections. The recommended regimens for MSSA SAB are as follows: nafcillin or oxacillin or methicillin 2 g every 6 hours administered intravenously (IV) or cefazolin 2 g every 8 hours IV. If the patient has no focus of infection, or foreign bodies, and has improved, a switch to once-daily ceftriaxone 2 g IV or cefazolin 2 g IV once daily with probenecid can be made.71 In the rare case (w5%), MSSA may be penicillin sensitive. In such cases, crystalline penicillin G, 4 million units every 4 hours, can be administered. In patients allergic to penicillin, cefazolin may be tolerated (5%30% anaphylactic cross reactivity). In case of anaphylactic reaction to penicillin, vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, clindamycin, or trimethoprim-sulfamethoxazole could be used as an alternative.
Antibiotic Combinations

Although in vitro testing and several endocarditis animal models have shown that the combination of beta-lactam and gentamicin, as well as vancomycin and gentamicin, may be synergistic and result in a more rapid bacterial killing, faster eradication of bacteremia and more complete sterilization of the vegetations, clinical evidence do not support these combinations (beta-lactam or vancomycin with an aminoglycoside). In fact, a randomized trial of 48 patients with MSSA native valve endocarditis; who received nafcillin plus gentamicin for the first 2 weeks of therapy had more rapid clearing of bacteremia in the first days of the combined regimen than those who received nafcillin alone. However, cure rates were comparable and the combination of nafcillin and gentamicin was associated with a higher incidence of renal dysfunction.72 A later randomized trial of 236 patients with SAB and endocarditis demonstrated that daptomycin monotherapy was not inferior to low-dose gentamicin plus an antistaphylococcal penicillin or vancomycin. Patients who received gentamicin had significantly more renal impairment than those in the daptomycin-only arm. There was also significantly greater reduction in creatinine clearance among those who received initial low-dose gentamicin than those who did not (22% vs 8%, respectively).73,74 Rifampin is also not indicated for the treatment of SAB, whether caused by MSSA or MRSA. An earlier clinical observation in patients with endocarditis showed that patients who received rifampin in addition to beta-lactam or vancomycin had longer duration of bacteremia.75 In addition, resistance to rifampin may develop during SAB therapy.76
MRSA SAB

Vancomycin has traditionally been considered the agent of choice for the treatment of severe MRSA infections (Table 2). New drugs have been added to the therapeutic

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Table 2 Threrapy of SAB Initial Therapy Pending Culture and Susceptibility Results Agents MSSA active BetaLactama 1 vancomycin MSSA Alternatives Daptomycinb, Telavancinc Linezolidd, Teicoplanine Nafcillin, oxacillin, flucloxacillin, cefazolin, cefuroxime, cefamandole, cefotaxime For Drug-Allergic/Intolerant Patients Cephalosporin 1 vancomycin, or vancomycin alone or telavancine, or linezolidd alone Cephalosporins or daptomycinb, or teicoplanin, or telavancine or linezolidd

MRSA (MIC to Vancomycin or daptomycinb Daptomycinb, teicoplanin or vancomycin <1.5 mg/L) telavancine or linezolidd, or quinupristin-dalfopristin hVISA VRSA Daptomycinb, telavancine Linezolid , telavancin quinupristin-dalfopristin
d e

Linezolidd, quinupristin-dalfopristin Linezolidd, telavancine quinupristindalfopristin

Abbreviations: hVISA, heteroresistant vancomycin intermediate S.aureus; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; SAB, Staphylococcus aureus bacteremia; VRSA, vancomycin resistant S.aureus. a Oxacillin, cloxacillin, methicillin, flucloxacillin, cefazolin, cefuroxime, ceftriaxone, cefotaxime. b Except when if originating from Community-acquired-pneumonia, Hospital-acquired pneumonia, Ventilator associated pneumonia (CAP/HAP/VAP). c Not yet marketed. d Not to be used when endocarditis is suspected. e Not if creatinine clearance <30 mL/min.

arsenal in the past years, and in the coming years we are likely to see still more new therapeutic agents. The efficacy of vancomycin has been debated, particularly in view of increasing vancomycin MIC of some strains of MRSA, the so-called vancomycin creep (the increase in MIC is from <1 mg/mL to w2.0 mg/mL). This laboratory phenomenon is accompanied by clinical failures of vancomycin treatment.7779 The vancomycin creep is not a general phenomenon and is limited to certain geographic areas. To ensure clinical success, the breakpoints of vancomycin for SA were lowered to the following: susceptible MIC, 2 mg/mL or less; intermediate MIC, 4 to 8 mg/mL; and resistant MIC, 16 mg/mL or more. The other parameter that is being discussed presently is whether the dose of vancomycin is high enough. Current guidelines64 recommend a loading dose and keeping trough serum vancomycin levels approximately 15 to 20 mg/mL in severe infections. Attempts to increase the dose of vancomycin, to obtain higher trough levels, have been met with a limited clinical success80,81and with additional nephrotoxicity, thus this approach is probably unjustified.81 Vancomycin is slowly bactericidal and has limited penetration to various tissues and organs, including the brain, the cerebrospinal fluid, and the pulmonary epithelial lining fluid. Alternatives to vancomycin should be considered in the setting of adverse effects to vancomycin or infection with a pathogen with inadequate susceptibility to vancomycin (MIC > 1 mg/mL) or in a vancomycin treatment failure (positive blood cultures after 48 hours of vancomycin therapy without a focus of infection). The current available alternatives are linezolid and daptomycin. Linezolid is a bacteriostatic, synthetic oxazolidinone antibiotic that inhibits the initiation of bacterial protein synthesis at the 50 S bacterial ribosome. It does not exhibit

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cross resistance with other protein synthesis inhibitors (tetracycline, clindamycin, and macrolides). Its mechanism of action may lead to enhanced efficacy against strains producing toxins, such as PVL, alpha-hemolysin, and the toxic shock syndrome toxin-1.82 Linezolid has excellent tissue distribution as well as excellent bioavailability, and may be administered parenterally or orally, reaching similar blood concentrations. Linezolid resistance and linezolid failure have been described,83,84 and in a case of MRSA endocarditis, resistance has been reported to have developed during treatment. An outbreak of linezolid-resistant MRSA has also been described in an intensive care setting.84 Linezolid treatment duration is limited to 28 days; adverse events that should be monitored carefully include thrombocytopenia, anemia, lactic acidosis, peripheral neuropathy, serotonin toxicity, and ocular toxicity, which tend to develop more frequently after use of this agent for 28 days or longer. Linezolid can reversibly inhibit monoamine oxidase; when administered with serotonergic agents and can induce the serotonin syndrome. Some of the adverse events are not reversible (ocular toxicity). Thrombocytopenia and lactic acidosis are more common in the setting of prolonged therapy and renal failure.85 It should be noted that in the settings of mixed MRSA and gram-negative bacteremia, linezolid should not be used, as higher mortality and failure rates were noted.86 Linezolid dosing is 600 mg every 12 hours IV or orally regardless of renal functions. Based on the previously mentioned toxicities, monitoring of blood counts and serum chemistries should be performed at least weekly during therapy. Linezolid can also occasionally be useful as oral therapy to complete a full course of treatment after initial therapy with vancomycin. Daptomycin is a cyclic lipopeptide bactericidal antibiotic that causes depolarization of the bacterial cell membrane. The use of daptomycin in the setting bacteremia with or without endocarditis due to MRSA and other selected gram-positive pathogens was subjected to a controlled study.73 The noninferiority of daptomycin compared with vancomycin plus low-dose gentamicin for SAB was demonstrated in a trial involving 246 patients with SAB with or without right-sided endocarditis (99 with MRSA).73 Successful outcomes were observed in 44% and 42%, respectively. In a post hoc analysis of this study, the investigators concluded that daptomycin may be considered as an alternative to standard therapy in the treatment of patients with SAB and osteoarticular infections. Daptomycin should not be used for treatment of MRSA pneumonia because its activity is inhibited by pulmonary surfactant. Daptomycin MIC may increase during therapy and may be influenced by previous exposure to vancomycin. In 6 of 19 patients with microbiologic failure while on daptomycin for SAB, the MIC for daptomycin increased from 0.25 to 0.5 mg/mL to 2.0 to 4.0 mg/mL.73 In addition, SA isolates exposed to vancomycin demonstrated daptomycin heteroresistance.87 Thus, daptomycin susceptibility testing is critical both before and during daptomycin therapy. Patients on daptomycin should be evaluated for peripheral neuropathy and myopathy by serial measurements of serum creatine kinase at least weekly. Daptomycin should be discontinued if symptomatic myopathy appears and creatinine-phospho-kinase (CPK) increases to 5 times or more the upper limit of normal (ULN) or in asymptomatic patients with CPK greater than or equal to 10 times ULN. Daptomycin has also been associated with eosinophilic pneumonia.88 The possibility of eosinophilic pneumonia due to daptomycin should be pursued when patients develop new onset of fever, pulmonary infiltrates, and/or eosinophilia. Quinupristin-dalfopristin is a potential alternative drug for the treatment of SAB, but several important factors limit its use. It requires central venous administration because of the risk of severe infusion-associated phlebitis in peripheral veins. Adverse events, such as hyperbilirubinemia, myalgias, and arthralgias, are common and can be

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severe.89 Development of resistance during treatment has been described in both SA and enterococci.90 Both linezolid and quinupristin-dalfopristin are occasionally useful for the treatment of SAB in patients with true allergy or severe intolerance to vancomycin. Other agents that might be used include trimethoprim-sulfamethoxazole (co-trimoxazole) with the caveat that the agents activity may be neutralized where undrained pus is present (abscess). Before clindamycin 600; mg every 8 hours can be used the laboratory D test should be performed on SA isolates and clindamycin should not be used when the isolates are D-zone positive, indicating the inducible MLS(B) form of resistance.91 Teicoplanin is used frequently as therapy for SAB in some European countries (dose 10 mg/kg once daily). It has similar in vitro activity to vancomycin and clinical trials have shown comparable results. Teicoplanin is associated with fewer side effects compared with vancomycin and is considered to be renal safe.92 Newer antibiotics that may reach the market in the coming years and have good activity against MRSA include telavancin, a lipoglycopeptide that is active against vancomycin resistance, heteroresistant SA (VISA and hVISA) and that requires only oncedaily administration. Telavancin has been approved in the United States for treatment of skin and soft tissue infections and is awaiting approval for the treatment of nosocomial pneumonia, but no formal study in SAB has been performed. Dalbavancin is a glycopeptide with an extremely long half-life that requires onceweekly administration and has a rapid onset of action with a rapid bacterial kill. Oritavancin is another glycopeptide with a very long half-life, and tedezolid, a second-generation oxazolidinone that unlike linezolid is bactericidal, and has once-daily administration (200 mg) and a better safety profile. These agents have not yet been studied systematically in patients with SAB. The treatment duration of SAB is a topic of some debate; earlier studies have suggested a prolonged course of treatment. A retrospective study of only 55 patients revealed that for uncomplicated (without any metastatic infection) catheter-associated blood stream infection caused by SA, the duration of treatment should be longer than 10 days but does not have to exceed 14 days.93 A more recent study94 of 244 patients with SAB was stratified by the relative risk for complications, and treatment was based on clinical criteria, including the absence or presence of a removable focus of infection, prosthetic material, and/or a deep focus of infection. In that study, the duration of antibiotic therapy was determined by a patient-specific approach incorporating clinical, microbiologic, and echocardiographic criteria and the clinical course monitored for evidence of complicated infection and the time to defervescence (maximum temperature <38.0 C). Along with follow-up blood cultures taken 2 to 4 days after the institution of therapy, these criteria were the determinants for establishing the length of therapy. Thus, a patient-specific approach is advised for determining the length of therapy. The following patients can be treated with 10 to 14 days of therapy: those in whom valvular abnormalities predisposing to endocarditis are absent; those who become afebrile without symptoms of metastatic infections within 72 hours after instituting effective antibiotic therapy; those whose follow-up blood cultures 2 to 4 days after instituting effective therapy are sterile; and in those individuals without any artificial devices including vascular grafts. Without the removal of an infected IV catheter (including Hemodialysis catheter, Hickman catheter, and so forth), the microbiological cure rate is very low (<20%)95 and relapse is high (w80%).70 Prompt removal of an infected catheter still leaves a small proportion of patients at risk to develop complications, such as endocarditis.96

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Cardiac artificial devices (pacemakers) are particularly prone to a complicated course of SAB; in one series the rate of confirmed device infections was 45.4%.20 Deep infected foci mandate a long treatment duration, as the risk for relapse is high (15%26%).70,94 In summary, SA and MRSA have emerged as the most important nosocomial pathogens. Traditional therapy may be sufficient in most but not all patients, in whom alternatives should be sought. The infection is often complicated with several sites of metastatatic foci and is nosocomial frequently. New antibiotics to fight MRSA have been introduced and are equivalent or better than vancomycin.
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