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.

Ethan Rubinstein,



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) 547–562 http://dx.doi.org/10.1016/j.ccc.2013.03.008 criticalcare.theclinics.com 0749-0704/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

organ invasion (particularly soft tissue and the lung). two-thirds caused by MRSA. and so forth all contribute singly or collectively to more severe courses.12 The presence of renal failure (odds ratio [OR] >12) and an underlying solid tumor predict intravascular complications.11 Microbial factors.9 More than one-third of these patients developed metastatic sequelae.6% in bacteremia of fewer than 2 days’ duration up to 38% in those with bacteremia of more than 4 days’ duration. both the underlying immunocompromised state. difficult to treat. Among patients with HIV. pathogenic elements. and . ranging from 30% to 40% in some reports. In a study from before the high-intensity antiretroviral therapy (HAART) era. and treatments may all contribute to an increased risk of complications. 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.3. and to a disease course that is more complicated.10 Individuals with SAB in the setting of underlying malignancy also have high rates of complications. skin findings suggesting acute systemic infection.4 episodes per 1000 patients. the incidence of a metastatic complication was 2.8 Higher rates of complications are seen among immunosuppressed patients. with mortality rates of up to 18% and a relapse rate of 15%. Fowler and colleagues5 went on to identify some of the predictors for occurrence of complication in a prospective cohort study. Supporting the first notion is a prospective study that correlated the presence of complications among 245 cases of SAB with duration of bacteremia. or CD4 count were not predictive of either endocarditis or in-hospital mortality.7 The presence of prosthetic devices is frequently implicated as the source for SAB. Nearly half developed endocarditis and the mortality rate was 8%. and positive follow-up blood cultures at 48 to 96 hours were useful for predicting complicated SAB. The most robust predictor was a persistent positive blood culture at 48 to 96 hours. the presence of hemolysin. metastatic infection. such as the previously mentioned PVL. 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). current receipt of antiretroviral therapy. of which more than half were attributed to CA-MRSA. 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). CA-MRSA was associated with endocarditis and mortality. the behavioral risk factors associated with HIV acquisition.11.5-fold lower with an identifiable source of bacteremia than among patients without an apparent source. the incidence of SAB among a large population of HIV-infected patients was 5.548 Keynan & Rubinstein seeding in community-associated (CA-SAB) versus hospital-associated SAB (HA-SAB). There was a linear association with rates of 6. preculture severity of illness. antibiotic susceptibility. as well as being an important risk factor for the development of complicated course. and the combination of 4 clinical parameters: community acquisition. In a series of 281 patients with SAB. but other comorbid conditions. A more contemporary study included 131 episodes of SAB. extended bacteremia. 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. persistent fever at 72 hours.6 The absence of an obvious source of bacteremia has been shown to serve an important predictor of subsequent complications. and subsequently leading to a higher mortality.

increased mortality.9% and 26.15 In a study of 241 patients diagnosed with SAB. blood pressure. The rate of complications and mortality both increased with higher APACHE scores (mortality rate of 44% in the 7–9 score. respiratory rate. SAB.29 19 30. Eleven presented with shock and.17 . of those. Both scores were found to be useful in predicting outcomes. 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. 10 (w90%) died. high mortality Complicated course. CURB-65.4% in men. Staphylococcus aureus bacteremia.12 11. the predictive capacity of Rapid Emergency Medicine Score (REMS) and the CURB-65 (confusion. blood pressure. respectively. increased relapse Aggravates and prolongs SAB Intravascular complications Intravascular complications Complicated course. with OR of 1. MRSA.21 9. septic shock. septic shock.54. The 30-day all-cause mortality was 39. and age 65) were assessed. urea. high mortality References 1–4 17 5 13 3. methicillin-resistant Staphylococcus aureus.5%.Staphylococcus aureus Bacteremia 549 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. urea. CURB-65 score higher than 3 or REMS higher than 6 at the first evidence of SAB correlated with attributable mortality rates of 34. 135 caused by methicillin-resistant and 106 with methicillin-susceptible isolates.12 14 16 18. Female sex remained an independent risk factor for 30-day mortality in a logistic regression analysis.10 11. high mortality High mortality High mortality Prolonged course Complicated course.8% compared with 35. septic shock.7 8. respiratory rate.31 32 Abbreviations: APACHE.3%. attributable mortality. 88% among those with APACHE II >10).16 An interesting cohort study of SAB included retrospective assessment of 1093 patients. A second series published in the same year found similar association between the APACHE score and subsequent mortality. A change in APACHE score of 7 or more had a positive predictive value of 53% and 83%. confusion.20. and age 65. for fatal and complicated outcomes. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has also been investigated as a potential tool for prediction of SAB complications. Higher rates of septic shock were seen among women and the mortality rate for women was 44. Acute Physiology and Chronic Health Evaluation. respectively.

it is important to recognize that some metastatic seeding may not become clinically evident for several weeks.30. supporting the notion that longer duration of bacteremia leads to higher rates of seeding. and CA-MRSA type USA 300 represented 56% of all MRSA isolates. Infective endocarditis (IE) is a frequent complication of SAB and carries a risk for severe sepsis. organ. of which 36% were postoperative and 64% represented hematogenous meningitis.24 They also showed that the incidence of vertebral involvement was higher in community-acquired cases. 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.18 These rates are even higher when a prosthetic valve is involved. and bacteremia. Although more commonly the result of intracranial surgery.28 A more recent series from the United States included 33 cases with SA meningitis.23. PVL was demonstrated. 3 times higher than the non-SA. . Other prosthetic devices are also important sites of SA seeding and permanent pacemakers and cardioverters-defibrillators. Patients with intravascular nidus of infection tend to have prolonged or persistent fever and recurrent or continuous episodes of bacteremia.29 Septic thrombophlebitis due to SA is usually an iatrogenic complication caused by an infected intravascular catheter or another device. who develop septic emboli to the lungs associated with tricuspid valve vegetation. and this complication is reported in up to 10% of cases in some series.550 Keynan & Rubinstein SYSTEMIC AND FOCAL END ORGAN COMPLICATIONS Virtually any tissue. The local clinical evidence of infection at the catheter site. with more than half of such devices becoming involved during SAB bacteremia. due to the privileged vascular supply to synovial tissue. Orthopedic prostheses are also at high risk of seeding during SAB bacteremia with rates of up to 34% reported. and sometimes hemoptysis.22 Although such metastatic sites of infection can appear early in the course of the infection. A study by John and colleagues19 documented cardiac complications in two-thirds of patients with SA PVE. The presence of cardiac complications was strongly associated with in-hospital mortality.31 Pulmonary complications of SAB occur more frequently among injection drug users. or foreign material can become the focus of dissemination and seeding during SAB. pleuritic chest pain. presenting with neck. One such site of hematogenous spread of SAB is the vertebral column.4 The most common joint involved is the knee. neurologic complications. in 2 series of patients with SA meningitis. between 27% and 34% of patients developed meningitis as a consequence of SAB.27. or signs of venous compromise (distal edema) may be lacking. involvement of extra-axial joints is not uncommon. especially in the critically ill patient who is unable to localize symptoms.20 The incidence of seeding of cardiac-assist devices during SAB remains to be determined. Several complications are worth mentioning. MRSA isolates accounted for nearly a half of the cases. In addition. facial deep-seated infection.25. and high mortality rates. Patients often present with fever. especially among patients older than 50 and the incidence increased in the latter period of the infection. Immunosuppression or preexisting rheumatic condition or previous joint damage provide a predilection for joint involvement during SAB. and central nervous system (CNS) complications were detected in a third.26 Seeding of the CNS may occur as a complication of SAB. Two studies from the same group of investigators from Denmark showed high rates of vertebral involvement.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. Cases of Lemierre syndrome. 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%.

disrupted blood flow. severe MRSA pneumonia also may develop.35 ADAM10 mediates proteolytic cleavage of the extracellular domain of vascular endothelial cadherin and disrupts its intercellular interactions. and thrombus formation. Dysfunctional endothelium plays a role in generation of the systemic inflammatory response and initiation of small-vessel thrombosis. lung abscesses.42. platelet degranulation. This interaction leads to platelet activation with ensuing platelet adhesion. Using a mouse model. IE. preventing bacterial tissue invasion. fibronectin A and B (FnBPA and FnBPB).36 leading to increased endothelial permeability. and elastin. with ensuing activation of the coagulation cascade. von Willebrand factor (vWF).43 Many studies have documented the role of staphylococcal surface adhesins in interacting with multiple pathways culminating in thrombus formation.44. leucopenia. A major culprit in SA-associated endothelial dysfunction is the staphylococcal a-hemolysin (SAHa). laminin. they not only illustrated this effect.33.Staphylococcus aureus Bacteremia 551 The presence of multiple nodular infiltrates should dictate directed history and diagnostic testing. directly through coagulation factors or through interaction with the vascular endothelium. which directly contributes to endothelial injury. tumor necrosis factor receptor-1. a pore-forming cytotoxin ubiquitously secreted by most strains of SA. vertebral osteomyelitis.38–40 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. sharing structural homology and binding affinities and mediating an interaction with extracellular matrix molecules. The management of such patients has been proven to benefit from the involvement of infectious diseases experts. It is widely expressed on the endothelium and regulates cellular adhesion and migration. causing bacteremia. but were also able to restore vascular integrity using an ADAM10 inhibitor. Similarly. aggregation. and dysfunctional endothelium mediate a decrease in tissue oxygenation. 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. and death. both proinflammatory mediators and pathogen-induced endothelial injury impairs the vessel integrity. epidural abscess. . Powers and colleagues37 examined the role of ADAM10 in toxin-mediated endothelial barrier disruption. These may serve as potential targets for future therapeutics. which may be difficult to recognize and which can lead to disability and to death.41 Another interaction is mediated by protein A. In addition. thereby leading to tissue invasion. thereby initiating thrombus formation.45 MANAGEMENT OF SA COMPARING THE PRE-ANTIBIOTIC ERA IN BACTEREMIA As mentioned earlier. and platelets. Among those are protein A. In patients with CA-MRSA infections complicating a preceding viral infection. SAB is also influenced by the ability of SA to activate coagulation through a myriad of interactions mediated by multiple bacterial proteins. and clumping factor A and B (ClfA and ClfB). discitis). patients with SAB can develop diverse complications (eg. it has been shown that protein A mediates a vWF-GP1b interaction. The combination of inflammation. empyema. vitronectin. It has been suggested that more virulent strains possess greater ability to mediate these endothelial and coagulation interactions.34 The A-disintegrin and metalloprotease 10 (ADAM10) has been recently identified as the receptor for SAHa. such as fibrinogen. During SAB. This surface adhesin is able to bind to the Fc fragment of antibodies.32 PATHOGENESIS The vascular endothelium serves as a barrier between the bloodstream and the tissues.

and spinal surgeons is helpful.aureus [VISA] with heteroresistance pattern to vancomycin). 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. the combination of nafcillin and vancomycin significantly improved antibacterial activity against hVISA (vancomycin intermediate susceptible S. 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. and whose fever and bacteremia resolve within 72 hours following removal of a likely focus (such as intravascular catheter).8% (a 22% reduction). Comparing the pre-antibiotic era to the era of effective antistaphylococcal antibiotics for HA-SAB. ceftriaxone).46–48 Before the introduction of effective antibiotics. such as matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry and DNA detection–based methods will allow for a more rapid . making TEE in these high-risk patients mandatory.5%–25. the mortality from SAB was approximately 80%. particularly for CA-SAB. cardiac surgeons. MRSA.aureus bacteremia (HA-SAB) lasting longer than 4 days. a similar picture prevails.59 Empiric Antibiotic Therapy Empiric therapy depends on the local epidemiologic data. we recommend a combination of anti-MSSA agent (eg. age. regardless of the mode of acquisition. whereas the change for CA-SAB was smaller (26.53 as the frequency of endocarditis in CA-SAB is high (w30%). methicillin. and MSSA compared with either drug alone. The reason for this recommendation is the superior activity of beta-lactams compared with vancomycin for MSSA60–62 combined with the fact that these antibiotics do not cover MRSA. cefazolin.49 Recent series have still shown a mortality rate of 20% to 40%. nonculture-based microbiologic-diagnostic methods.52 The guidelines of the Infectious Diseases Society of America recommend echocardiography for every case of SAB. In the absence of controlled clinical trials that specifically address this issue.8% to 21. spinal infection. female sex. functional score. and vancomycin should be administered pending susceptibility results.55–58 Exceptions are patients who are young and previously healthy who have no underlying cardiac predisposing conditions or clinical signs of endocarditis. the involvement of cardiologists. By multivariate Cox regression.8%).50 In Australian aboriginals. The presence of a permanent intracardiac device. and alcohol-related diagnoses were associated with increased mortality in a European series. hemodialysis dependency.65 It is hoped that in the not too distant future. time period. cefuroxime. crude 30-day mortality decreased from 27. Of note is that some patients in the intensive care unit may have higher volume of distribution of vancomycin and accelerated clearance.63 Furthermore. similarly.552 Keynan & Rubinstein when cardiac complications or spinal involvement arise.64 Serum trough concentrations should be monitored and the dose adjusted to obtain trough levels of approximately 12 to 17 mg/mL. In a new publication describing in vitro experiments. flucloxacillin. 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.51 In the United States. thus resulting in 33% lower than recommended vancomycin in the area under the time concentration curve. oxacillin. no antagonism between these 2 agents is known for any pathogen. particularly for HA-SAB. or nonvertebral osteomyelitis have a high association with endocarditis. particularly in the phase of fluid resuscitation. in which an echocardiogram is essential. the incidence of CA-SAB increased while mortality (due to young age) decreased.54 The transesophageal echocardiogram (TEE) provides more information than the transthoracic echocardiogram (TTE) and is the preferred diagnostic modality.

MSSA may be penicillin sensitive. faster eradication of bacteremia and more complete sterilization of the vegetations. may be synergistic and result in a more rapid bacterial killing. the relapse rate of MSSA when treated with vancomycin is far higher than when treated with betalactams (odds ratio 4.67 As discussed previously. Antibiotic Combinations Although in vitro testing and several endocarditis animal models have shown that the combination of beta-lactam and gentamicin.69 In addition. In case of anaphylactic reaction to penicillin. In fact. quinupristin-dalfopristin. cefazolin may be tolerated (5%–30% anaphylactic cross reactivity).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.68. a switch to once-daily ceftriaxone 2 g IV or cefazolin 2 g IV once daily with probenecid can be made. In such cases. In patients allergic to penicillin. such as cefazolin and cefuroxime or cefamandole as their first choice. 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%. vancomycin. a fraction of MSSA show increased vancomycin MIC contributing to the decreased success rate of vancomycin in MSSA infections.75 In addition. clinical studies have shown that the anti-staphylococcal activity of all these agents is similar. Some centers use first-generation and second-generation cephalosporins. oxacillin. When susceptibilities of SA become known. linezolid.Staphylococcus aureus Bacteremia 553 identification of SA and rapid determination of whether it is MSSA or MRSA through the detection of the mecA gene. respectively). vancomycin should not be used for MSSA infections because of its inferior clinical results in systemic MSSA infections. Patients who received gentamicin had significantly more renal impairment than those in the daptomycin-only arm. 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. 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.71 In the rare case (w5%). or flucloxacillin are the agents of choice. cure rates were comparable and the combination of nafcillin and gentamicin was associated with a higher incidence of renal dysfunction. daptomycin.66 There is little difference between the various cephalosporins of the first and second generation with regard to clinical effects in MSSA bacteremia. whether caused by MSSA or MRSA. 4 million units every 4 hours. or foreign bodies. as well as vancomycin and gentamicin.70 Further. clindamycin. and has improved. a more focused therapy becomes feasible. If the patient has no focus of infection. confidence interval 1.74 Rifampin is also not indicated for the treatment of SAB.1. or trimethoprim-sulfamethoxazole could be used as an alternative.6). a randomized trial of 48 patients with MSSA native valve endocarditis. including MSSA SAB. resistance to rifampin may develop during SAB therapy. nafcillin. clinical evidence do not support these combinations (beta-lactam or vancomycin with an aminoglycoside). However.73. 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. If the organism is MSSA.76 MRSA SAB Vancomycin has traditionally been considered the agent of choice for the treatment of severe MRSA infections (Table 2). crystalline penicillin G.5–11. New drugs have been added to the therapeutic . can be administered.

To ensure clinical success. The efficacy of vancomycin has been debated. MIC. cefuroxime. 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). and in the coming years we are likely to see still more new therapeutic agents. have been met with a limited clinical success80. the cerebrospinal fluid. oxacillin. This laboratory phenomenon is accompanied by clinical failures of vancomycin treatment. vancomycin resistant S. flucloxacillin.554 Keynan & Rubinstein Table 2 Threrapy of SAB Initial Therapy Pending Culture and Susceptibility Results Agents MSSA –active BetaLactama 1 vancomycin MSSA Alternatives Daptomycinb. or quinupristin-dalfopristin hVISA VRSA Daptomycinb. cefotaxime. or telavancine or linezolidd MRSA (MIC to Vancomycin or daptomycinb Daptomycinb. ceftriaxone. b Except when if originating from Community-acquired-pneumonia. a Oxacillin. e Not if creatinine clearance <30 mL/min. heteroresistant vancomycin intermediate S.81 Vancomycin is slowly bactericidal and has limited penetration to various tissues and organs. Linezolid is a bacteriostatic. Current guidelines64 recommend a loading dose and keeping trough serum vancomycin levels approximately 15 to 20 mg/mL in severe infections. 2 mg/mL or less.aureus. arsenal in the past years. c Not yet marketed. Hospital-acquired pneumonia. Telavancinc Linezolidd. or vancomycin alone or telavancine. to obtain higher trough levels. The other parameter that is being discussed presently is whether the dose of vancomycin is high enough. telavancine Linezolid . cloxacillin. d Not to be used when endocarditis is suspected. Attempts to increase the dose of vancomycin. methicillin-resistant Staphylococcus aureus. VRSA. telavancine quinupristindalfopristin Abbreviations: hVISA. MSSA. or linezolidd alone Cephalosporins or daptomycinb. It does not exhibit . particularly in view of increasing vancomycin MIC of some strains of MRSA. thus this approach is probably unjustified. cefamandole. intermediate MIC. methicillin-susceptible Staphylococcus aureus. cefazolin. methicillin. or teicoplanin. The current available alternatives are linezolid and daptomycin.0 mg/mL).aureus. cefazolin. teicoplanin or vancomycin <1. cefotaxime For Drug-Allergic/Intolerant Patients Cephalosporin 1 vancomycin. Teicoplanine Nafcillin. quinupristin-dalfopristin Linezolidd.5 mg/L) telavancine or linezolidd. 4 to 8 mg/mL. telavancin quinupristin-dalfopristin d e Linezolidd. minimal inhibitory concentration. 16 mg/mL or more. SAB.77–79 The “vancomycin creep” is not a general phenomenon and is limited to certain geographic areas. the breakpoints of vancomycin for SA were lowered to the following: susceptible MIC. synthetic oxazolidinone antibiotic that inhibits the initiation of bacterial protein synthesis at the 50 S bacterial ribosome. cefuroxime. the so-called “vancomycin creep” (the increase in MIC is from <1 mg/mL to w2.81and with additional nephrotoxicity. and the pulmonary epithelial lining fluid. flucloxacillin. including the brain. and resistant MIC. MRSA. Staphylococcus aureus bacteremia. Ventilator associated pneumonia (CAP/HAP/VAP).

Quinupristin-dalfopristin is a potential alternative drug for the treatment of SAB. 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. the investigators concluded that daptomycin may be considered as an alternative to standard therapy in the treatment of patients with SAB and osteoarticular infections. alpha-hemolysin. It requires central venous administration because of the risk of severe infusion-associated phlebitis in peripheral veins. Adverse events.5 mg/mL to 2.73 Successful outcomes were observed in 44% and 42%.Staphylococcus aureus Bacteremia 555 cross resistance with other protein synthesis inhibitors (tetracycline. Some of the adverse events are not reversible (ocular toxicity). and arthralgias. Linezolid can also occasionally be useful as oral therapy to complete a full course of treatment after initial therapy with vancomycin. Patients on daptomycin should be evaluated for peripheral neuropathy and myopathy by serial measurements of serum creatine kinase at least weekly. lactic acidosis. 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. Its mechanism of action may lead to enhanced efficacy against strains producing toxins. An outbreak of linezolid-resistant MRSA has also been described in an intensive care setting.82 Linezolid has excellent tissue distribution as well as excellent bioavailability.25 to 0. myalgias. as higher mortality and failure rates were noted. but several important factors limit its use.84 Linezolid treatment duration is limited to 28 days. anemia. resistance has been reported to have developed during treatment. such as PVL.73 In addition. and may be administered parenterally or orally. adverse events that should be monitored carefully include thrombocytopenia. Thrombocytopenia and lactic acidosis are more common in the setting of prolonged therapy and renal failure. serotonin toxicity.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). respectively.84 and in a case of MRSA endocarditis. Daptomycin should not be used for treatment of MRSA pneumonia because its activity is inhibited by pulmonary surfactant.83.85 It should be noted that in the settings of mixed MRSA and gram-negative bacteremia. linezolid should not be used. daptomycin susceptibility testing is critical both before and during daptomycin therapy. are common and can be . Linezolid resistance and linezolid failure have been described. and the toxic shock syndrome toxin-1. SA isolates exposed to vancomycin demonstrated daptomycin heteroresistance. Linezolid can reversibly inhibit monoamine oxidase. In a post hoc analysis of this study. clindamycin.88 The possibility of eosinophilic pneumonia due to daptomycin should be pursued when patients develop new onset of fever. Daptomycin has also been associated with eosinophilic pneumonia.87 Thus. peripheral neuropathy. which tend to develop more frequently after use of this agent for 28 days or longer. when administered with serotonergic agents and can induce the serotonin syndrome. the MIC for daptomycin increased from 0. and macrolides). Based on the previously mentioned toxicities. Daptomycin MIC may increase during therapy and may be influenced by previous exposure to vancomycin. and ocular toxicity. and/or eosinophilia. monitoring of blood counts and serum chemistries should be performed at least weekly during therapy.86 Linezolid dosing is 600 mg every 12 hours IV or orally regardless of renal functions.0 to 4. such as hyperbilirubinemia. reaching similar blood concentrations. pulmonary infiltrates. In 6 of 19 patients with microbiologic failure while on daptomycin for SAB.0 mg/mL. Daptomycin is a cyclic lipopeptide bactericidal antibiotic that causes depolarization of the bacterial cell membrane.

and echocardiographic criteria and the clinical course monitored for evidence of complicated infection and the time to defervescence (maximum temperature <38. such as endocarditis. those who become afebrile without symptoms of metastatic infections within 72 hours after instituting effective antibiotic therapy. earlier studies have suggested a prolonged course of treatment. and tedezolid. Before clindamycin 600.89 Development of resistance during treatment has been described in both SA and enterococci. Hickman catheter. Thus. a second-generation oxazolidinone that unlike linezolid is bactericidal. A retrospective study of only 55 patients revealed that for uncomplicated (without any metastatic infection) catheter-associated blood stream infection caused by SA. Without the removal of an infected IV catheter (including Hemodialysis catheter. In that study.0 C). heteroresistant SA (VISA and hVISA) and that requires only oncedaily administration. these criteria were the determinants for establishing the length of therapy. Oritavancin is another glycopeptide with a very long half-life. microbiologic. including the absence or presence of a removable focus of infection. and treatment was based on clinical criteria. and in those individuals without any artificial devices including vascular grafts. those whose follow-up blood cultures 2 to 4 days after instituting effective therapy are sterile. 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. the microbiological cure rate is very low (<20%)95 and relapse is high (w80%). indicating the inducible MLS(B) form of resistance. Along with follow-up blood cultures taken 2 to 4 days after the institution of therapy.556 Keynan & Rubinstein severe. 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.91 Teicoplanin is used frequently as therapy for SAB in some European countries (dose 10 mg/kg once daily).93 A more recent study94 of 244 patients with SAB was stratified by the relative risk for complications. It has similar in vitro activity to vancomycin and clinical trials have shown comparable results. These agents have not yet been studied systematically in patients with SAB. and so forth). The following patients can be treated with 10 to 14 days of therapy: those in whom valvular abnormalities predisposing to endocarditis are absent. Teicoplanin is associated with fewer side effects compared with vancomycin and is considered to be renal safe. and has once-daily administration (200 mg) and a better safety profile. 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. but no formal study in SAB has been performed. Other agents that might be used include trimethoprim-sulfamethoxazole (co-trimoxazole) with the caveat that the agent’s activity may be neutralized where undrained pus is present (abscess). the duration of treatment should be longer than 10 days but does not have to exceed 14 days.90 Both linezolid and quinupristin-dalfopristin are occasionally useful for the treatment of SAB in patients with true allergy or severe intolerance to vancomycin. the duration of antibiotic therapy was determined by a patient-specific approach incorporating clinical. The treatment duration of SAB is a topic of some debate. a lipoglycopeptide that is active against vancomycin resistance. and/or a deep focus of infection.70 Prompt removal of an infected catheter still leaves a small proportion of patients at risk to develop complications.92 Newer antibiotics that may reach the market in the coming years and have good activity against MRSA include telavancin. a patient-specific approach is advised for determining the length of therapy. prosthetic material.96 .

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