Management of Gram-Positive Coccal Bacteremia and Hemodialysis

Transcription

1 In Practice Management of Gram-Positive Coccal Bacteremia and Hemodialysis Lynn N. Fitzgibbons, MD, 1 Darcy L. Puls, MD, 1 Kimberly Mackay, PharmD, 2 and Graeme N. Forrest, MBBS 3 Gram-positive cocci are the most common cause of bloodstream infections in hemodialysis patients, with Staphylococcus aureus and coagulase-negative staphylococci causing most infections. Management of these infections often is complicated by limited vascular access options, as well as an increasing prevalence of drug-resistant bacteria in hemodialysis centers, including the emergence of strains of methicillin-resistant S aureus with vancomycin heteroresistance and increasing rates of vancomycin-resistant enterococci, both of which have limited antibiotic treatment options. This article describes the management of these infections based on the organism and its susceptibility profile, including catheter management, antibiotic lock therapies, and systemic antibiotic choices. Although coagulase-negative staphylococci bacteremia often may be managed with preservation of the catheter, antibiotic lock therapy, and intravenous antibiotics, this is rarely the case with S aureus bacteremia because of frequent relapse and the risk of complications, including endocarditis. Enterococcal bacteremia requires more individualization of care, but catheters are less likely to be salvaged, especially when vancomycin-resistant Enterococcus is the causative organism. Finally, strong infection control policies in the hemodialysis unit, conversion from catheter to arteriovenous access when possible, and appropriate use of antibiotics are essential factors in the prevention of these bloodstream infections. Am J Kidney Dis. 57(4): Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. INDEX WORDS: Staphylococcus aureus; hemodialysis; Enterococcus; catheter-related bacteremia; dialysis access related infection. CASE PRESENTATION A 46-year-old woman with a history of diabetes mellitus and end-stage renal disease caused by polycystic kidney disease receiving hemodialysis presents to dialysis with several days of fever and malaise. A screening nasal swab 6 months ago had shown methicillin-resistant Staphylococcus aureus (MRSA). Her hemodialysis is performed using a tunneled right internal jugular vein catheter that has been in place for 1 year and is functioning normally. She has not had another vascular access created. On examination, she is febrile and appears moderately ill. Cardiovascular examination is significant for tachycardia with a regular rhythm, and no murmurs are heard. The catheter exit site is unremarkable. Peripheral white blood cell count is / L ( /L) with 91% polymorphonuclear cells. She is admitted to the hospital, where blood cultures are drawn and empiric broad-spectrum antibiotic therapy is started. On hospital day 2, blood cultures are growing Gram-positive cocci. From the 1 Division of Infectious Diseases, Oregon Health and Science University; and 2 Department of Pharmacy and 3 Division of Infectious Diseases, Portland VA Medical Center, Portland, OR. Received August 31, Accepted in revised form December 13, Originally published online February 18, Address correspondence to Graeme N. Forrest, MBBS, Portland VA Medical Center, Division of Infectious Diseases, 3701 SW US Veterans Hospital Rd, P3-ID, Portland, OR forrestg@ohsu.edu Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use /$0.00 doi: /j.ajkd INTRODUCTION Infection is the second most common cause of mortality in hemodialysis patients, accounting for about one-quarter of all deaths. 1 In addition, infections are the leading cause of all hospital admissions (102 admissions/1,000 patient-years) in hemodialysis patients, with rates twice those appreciated in peritoneal dialysis patients. Notably, infections are associated with excessive costs for both the patient and hospital. 1-3 Of the Gram-positive organisms that cause hemodialysis-associated infections, S aureus and coagulase-negative staphylococci (CoNS) account for most infections, but enterococcal infections are increasingly observed. 4-8 Management of Gram-positive bloodstream infections (BSIs) in hemodialysis patients frequently is complicated by the limited vascular access options. 9 Additionally, the emergence of decreased vancomycin susceptibility of these organisms is another important consideration The objective of this article is to review current issues in the management of Gram-positive BSIs in hemodialysis patients. These include epidemiologic factors, pathogenesis, microbiological diagnosis, and treatment of staphylococcal and enterococcal infections. Streptococcal bacteremia is not discussed because it more often is due to an endogenous source and less frequently presents the complexity of management inherent in either staphylococcal or enterococcal bacteremia. 624

2 Gram-Positive Bacteremia and Hemodialysis Table 1. Staphylococcus aureus Phenotypes Associated With Hemodialysis Patients S aureus Phenotype Description Comment camrsa hvisa Also known as USA 300 strain; some may produce PVL Responsible for 18%-28% of hospital-related infections 26 ; toxin 24 associated with severe skin infections; bacteremia severity not increased MRSA with decreased susceptibility to vancomcyin; hvisa has subpopulations of MRSA with vancomycin MIC 2 g/ml and may be missed by automated testing 27,28,a Rates of hvisa reported at 20% (range, 18%-43%) in some centers 29 ; associated with 2.4 increased failure with vancomycin therapy 30 VISA MRSA with vancomycin MIC of 4-8 g/ml 28 Uncommon, usually due to prolonged use of vancomycin causing increased cell wall thickness 28,29 VRSA MRSA with vancomycin MIC 16 g/ml 28 Usually acquired VanA gene from VRE; very uncommon, but 50% of cases occurred in hemodialysis patients 29,31 Abbreviations: camrsa, community-acquired MRSA; hvisa, heterogeneous vancomycin intermediate S aureus; MIC, minimal inhibitory concentration; MSSA, methicillin-sensitive S aureus; MRSA, methicillin-resistant S aureus; PVL, panton valentine leukocidin; VISA, vancomycin-intermediate S aureus; VRSA, vancomycin-resistant S aureus; VRE, vancomycin-resistant Enterococcus. a Some MSSA strains may have increased vancomycin MICs. EPIDEMIOLOGY Bacteremia with Gram-positive cocci is a relatively common occurrence in patients receiving hemodialysis. 1,12-14 In a large prospective surveillance study of BSIs in Canadian hemodialysis centers, S aureus and CoNS each accounted for about 36% of infections, with enterococci following at only 9%. Of note, S aureus resulted for most arteriovenous (AV) access infections. 12 Historically, the incidence of catheterrelated bacteremia in hemodialysis patients ranged from episodes/100 patient-years, with S aureus accounting for 56% of these episodes S aureus S aureus is associated with the greatest mortality and cost of all BSIs in hemodialysis patients. 3,15 Several studies have shown costs to treat S aureus catheter-related bacteremia in hemodialysis patients to be US $23,000-$32,000, with mortality rates ranging from 15%-25% and significantly higher mortality for MRSA than methicillin-sensitive S aureus (MSSA) infection. 6,15,18-22 There has been a major shift in the epidemiologic characteristics of S aureus BSIs during the past decade, with MRSA now the dominant strain in many communities, although significant geographic variability is present and most MRSA infections are acquired nosocomially MRSA types and rates encountered in hemodialysis patients are listed in Table 1. Compared with MSSA BSI, MRSA is associated with higher mortality (2.2-fold increase), increased median hospital length of stay, and increased hospital costs. 18,32 The risk of MRSA BSI in hemodialysis patients is 100-fold higher than in the general population (45.2 vs 0.4 episodes/1,000 patient-years), with dialysis patients accounting for up to 15% of all invasive MRSA infections. 33 Despite this, there has been a decrease in rates of MRSA BSI in some regions of the world because of aggressive campaigns for the earlier conversion from catheter to AV access. 8 One consequence of the increased prevalence of MRSA BSI has been increased vancomycin use and the emergence of a heterogeneous vancomycin intermediate S aureus (hvisa) phenotype. These VISA strains have a slower growth rate and increased thickness of the outer wall, making vancomycin less permeable into the organism 27,34 (Fig 1). Hemodialysis patients also have been the first group to report nonsusceptibility to newer antibiotics, such as daptomycin and linezolid The emergence of these resistant strains within the hemodialysis population will limit future treatment options. Complications, such as endocarditis and metastatic infections, from S aureus BSIs in hemodialysis patients are frequent. 38 Mortality in hemodialysis patients with infective endocarditis from S aureus approaches 50%, although undergoing heart valve surgery appears to be associated with a survival benefit versus nonsurgical management. 39 Other serious infectious sequelae include septic arthritis, vertebral osteomyelitis, and infection of other intravascular devices, such as pacemakers and intracardiac defibrillators. 5,40 When S aureus BSI persists or recurs, searching for an ongoing nidus of infection is critical to minimizing the risk of the mentioned complications. 41 Coagulase-Negative Staphylococci CoNS bacteremia is the most common nosocomial BSI in the hemodialysis unit and accounts for up to 35% of positive blood culture results The proportion of blood cultures with CoNS has grown rapidly during the last 20 years, is greater in the United States than in Europe, and is associated with higher severity 625

3 Fitzgibbons et al Figure 1. Electron micrographs of Staphylococcus aureus magnified 348,000 times. (Left) Methicillinresistant S aureus from Georgia shows a normal cell wall without increased extracellular material; (right) glycopeptide (vancomycin)-intermediate S aureus from Michigan (hemodialysis patient) in which there is increased extracellular material. Panels reproduced from Smith et al 34 with permission of the Massachusetts Medical Society. of illness, elderly age, and intravascular catheters. 46,47 A major challenge with the reporting of CoNS in blood cultures is distinguishing contamination from true infection, with contamination likely responsible for 80% of results. 46,48,49 The significance of CoNS in blood cultures is complicated for 2 reasons: (1) frequent reliance on catheter-derived blood cultures, and (2) CoNS are rarely identified to the species level, although some species may have more serious invasive potential (eg, Staphylococcus lugdunensis). 9,46,47,50 More than 95% of nosocomial CoNS BSIs are methicillin resistant, and similar to hvisa strains, there is increasing vancomycin tolerance within some CoNS strains Although CoNS BSI is associated with less mortality than S aureus, complications can be similar and include endocarditis, vertebral osteomyelitis, and device infections. 41,50,51 Enterococci Enterococci are the fourth most common cause of nosocomial BSI in the United States. 14,42 There are 2 major enterococcal organisms: (1) Enterococcus faecalis, which usually is ampicillin and vancomycin susceptible, and (2) Enterococcus faecium, which usually has ampicillin resistance and high-level gentamicin resistance and is becoming increasingly vancomycin resistant. 42,54,55 Enterococcal bacteremia typically is suspected to emerge endogenously from a gastrointestinal source; however, vancomycin-resistant enterococci (VRE) has been spread within hemodialysis units from patient to patient, enhanced by poor infection control practices. 6,51,54 Complications of enterococcal infections in hemodialysis patients are similar to those for S aureus, including endocarditis and metastatic infection. 14 E faecalis occurs 3 times more frequently than E faecium, but E faecium rates are increasing. 6,42,54-56 Although E faecium accounts for 5% of bloodstream isolates, 65%-95% of these isolates are vancomycin resistant. 42,56 Risk factors described for VRE acquisition in hemodialysis patients include prolonged hospital stays, nonambulatory status, and prolonged vancomycin and -lactam antibiotic use. 6,54 VRE infections have limited treatment options and increased mortality compared with non-vre infections. 11,56 Taking action to prevent environmental and health care worker exposure by cohorting colonized and infected patients may be critical in a dialysis unit. 6,57 PATHOGENESIS Infection Risk in Hemodialysis Patients Patients with uremia have an altered response to infections, with deficits in cell-mediated immunity, phagocytosis by neutrophils, and antibody production In addition, diabetes, other immunosuppression, and dialyzer bioincompatibility may further depress these responses. 16,59 Additional factors that can increase the risk of infection include type of vascular access, presence of iron overload, and use of less pure dialysate Colonization S aureus colonization occurs in the anterior nares; 20% of healthy adults have persistent S aureus nasal carriage, whereas up to 30% are intermittent carriers and the rest are persistent noncarriers. 64,65 Several studies have suggested that 80% of S aureus BSIs come from an endogenous source of infection and that treating the carrier status is important in the prevention of invasive disease. 65,66 Other data have shown that environmental factors may have an important role because S aureus can survive for several weeks on surfaces Hemodialysis patients have a high rate 626

4 Gram-Positive Bacteremia and Hemodialysis of persistent and intermittent nasal S aureus carriage, and this is associated with an up to 4.7-fold increased risk of BSI with S aureus. 66,68,70 Molecular typing studies confirm that colonization with MRSA often precedes invasive infection. Therefore, prevention of transmission with hand hygiene in dialysis units is imperative to prevent transmission to other patients. 64,68,69,71-74 Other recognized risk factors for S aureus BSI in hemodialysis patients include older age, higher Karnovsky index score, type of vascular access, use of immunosuppressive therapy, use of iron therapy, and poor hygiene. 16,75-78 Biofilms A complete discussion of the pathogenesis of BSI is outside the scope of this review, but understanding biofilms is essential for the management of bacteremia in the dialysis population, for which decisions about catheter or other hardware removal or retention can be challenging. Bacterial colonization precedes biofilm formation on prosthetic material, such as dialysis catheters. 79,80 A biofilm has been defined as a structured community of bacterial cells enclosed in a self-produced polymeric matrix adherent to an inert or living surface 81(p1318) (Fig 2). 82 Bacteria within these communities are 100-1,000 times less susceptible to antibiotics compared with their planktonic (or free-growing) forms that are cultured on plates, and there is a concurrent neutrophil defect that affects phagocytosis of organisms within the biofilm Although antibiotics may suppress infection within a biofilm for a time, relapse is likely to occur, frequently with an antibiotic-resistant organism, unless there is removal of the device. 86 MANAGEMENT: GENERAL PRINCIPLES Prevention of hemodialysis-associated infections is central to decreasing antibiotic use and consequently decreasing the development of antibiotic resistance. Figure 2. Scanning electron micrograph of Staphylococcus epidermidis biofilm on foreign material. Reproduced from Zimmerli et al 82 with permission of the Massachusetts Medical Society. Catheter and AV Access Handling Standardized central catheter insertion recommendations have been developed to prevent infection. 87 Insertion using a maximally aseptic technique and barrier protection with the use of gloves, gown, and mask have significantly decreased catheter-related bacteremia regardless of the catheter type. 87 The preferred topical antiseptic appears to be a 2% chlorhexidine gluconate solution, and the type of dressing can be either clear gauze or polyurethane. 88 The position of the catheter also is critical, with femoral sites generally associated with increased risk of infection compared with jugular or subclavian catheters. 89 However, in the acute hemodialysis setting, body habitus correlates with the site of highest infection risk. Infection risk for patients with a body mass index 28.2 m/kg 2 is greater in the femoral site, whereas in patients with body mass index 24 m/kg 2, risk is greater in the jugular site. 90 Use of antibiotic-impregnated catheters may be beneficial in some patients with recurrent infections or limited vascular access, but are likely to be too expensive for routine use. 91,92 Proper cannulation of AV access also is critical and has decreased infections at these sites. 93 Similarly, personal barrier protection and site-care techniques should be used before cannulation of an AV site. 93 Local Antibiotic/Antiseptic Applications Use of mupirocin for nasal decolonization of S aureus carriers remains controversial despite apparent short-term benefits. 94 Several studies have shown that mupirocin nasal decolonization can eradicate nasal carriage and may decrease S aureus BSIs by up to 4-fold. 68,95 However, rapid relapse of S aureus colonization or reinfection, as well as the emergence of mupirocin resistance, is a concern with this strategy. 68,94,96 Application of topical mupirocin ointment thrice weekly to the exit site of tunneled catheters was associated with significant decreases in catheterrelated bacteremia in 2 small studies. 95,97 Other topical applications that have shown benefit in decreasing catheter-related bacteremia when applied thrice weekly to the exit site of tunneled catheters include povidoneiodine ointment, Polysporin (Johnson & Johnson Inc, and medical grade honey Catheter Lock Solutions Instillation of antibiotic solutions into tunneled catheters after hemodialysis can be used as a method to prevent biofilm formation and subsequently decrease infections. 101,102 Catheter-locking solutions that have been used include 1.35% taurolidine with 4% sodium citrate or gentamicin and/or minocycline and 627

5 Fitzgibbons et al cefazolin Meta-analyses have shown significant risk reduction of catheter-related bacteremia, especially when using gentamicin, with no evidence of resistance emerging. 102,104 Despite the low volume of antibiotic instilled, toxicity should be considered in its use because there is evidence for demonstrable systemic levels of gentamicin in hemodialysis patients when gentamicin-containing lock solutions are used. 105 These data suggest that catheter lock solutions may be beneficial in the prevention of catheter-related bacteremia in some hemodialysis patients. Vaccines Efforts to prevent S aureus infection in the highrisk hemodialysis population led to the development of a conjugate vaccine using the S aureus capsular polysaccharides 5 and 8 linked to a carrier protein (StaphVAX from Nabi Pharmaceuticals). Although this vaccine induced significant antibody levels, clinical studies showed only a 26% decrease in S aureus bacteremia at 1 year. This was believed to be insufficiently significant to expand its use, and as a result, the vaccine was discontinued. 106,107 New Molecular Diagnostics of BSI Early identification of Gram-positive organisms can direct the management of patients with BSIs. Staphylococcal species appear as Gram-positive cocci in clusters on Gram stain, whereas enterococcal species are Gram-positive cocci in pairs and chains and are indistinguishable from streptococcal species. Using traditional microbiological methods, speciation cannot occur until growth occurs on a plate, which can take hours. Newer molecular technologies now can identify these species within a few hours. 56, Two molecular technologies have become available for laboratories to rapidly identify organisms from blood cultures in a few hours: real-time polymerase chain reaction (PCR) and peptide nucleic acid fluorescent in situ hybridization (PNA FISH). Real-Time PCR There currently are 2 commercial platforms available that can rapidly identify either MRSA or MSSA from blood cultures by identifying the meca gene, which confers methicillin resistance. 108,109,111 These tests are 100% sensitive and 98.4% specific, with a positive predictive value of 92.6% and negative predictive value of 100%. 109,111 Importantly, rapid MRSA identification in the blood of a hemodialysis patient could expedite the initiation of appropriate therapies and guide more prompt removal of the dialysis catheter, if applicable. PNA FISH There currently is 1 approved PNA FISH testing platform. This system uses probes targeted against 16S ribosomal RNA to rapidly and accurately identify organisms from blood within 3 hours. The limits of detection are less than those for real-time PCR; however, there currently are probes that can identify S aureus from CoNS and E faecalis from other enterococci directly from Gram stain. 112 These probes cannot determine resistance, but local antibiograms can be used to direct therapy. Several studies have shown decreases in antibiotic use and patient mortality by directing antibiotic therapy earlier using these tests. 56,113 Both real-time PCR and PNA FISH technologies are expensive. However, earlier knowledge of the infecting organism that facilitates prompt initiation of targeted therapy could affect patient outcomes. 56 Defining Infection Source Initial steps in the management of Gram-positive cocci bacteremia in hemodialysis patients include bacterial identification and control of the source of infection. In the absence of localizing symptoms, management should include repeated blood cultures and assessment of all active and nonfunctioning intravascular catheters and devices (hemodialysis catheter, presence of synthetic material from current or prior AV access, pacemaker, prosthetic heart valves, and prosthetic joints). 16 Uncontrolled sites of primary infection can include nonprosthetic materials with high bacterial burden that are relatively protected from immune response because of either poor vascular supply or the propensity for biofilm formation (eg, chronic osteomyelitis, abscesses, and infected heart valves). Investigation into a nidus of ongoing infection with positive blood culture results should begin with a thorough history and examination. Although endovascular infections are the most common source of bacteremia, persistently positive blood culture results should raise the question of metastatic infection to sites, such as spinal vertebrae, joint spaces, and lungs, or seeding of a venous thrombus causing septic thrombophlebitis. Through vigilant clinical assessment and reassessment, additional sites of infection often are discovered. When an infectious source has been identified, early control is important. This may involve surgical assessment and intervention, including abscess drainage, removal of prosthetic materials, or debridement of infected bone

6 Gram-Positive Bacteremia and Hemodialysis Additional Diagnostic Testing Echocardiography: Transthoracic and Transesophageal Echocardiograms Infective endocarditis is a recognized complication of S aureus BSI, but also should be considered in patients with persistent CoNS or enterococcal bacteremia for which no other source for infection is found. 4,9,116,117 The 2005 American Heart Association guidelines for the management of valvular heart disease recommend initial transesophageal echocardiography in hemodialysis patients for diagnosing and managing S aureus infective endocarditis. 118 Although transthoracic echocardiography can detect larger vegetations, it is less sensitive (20%-60%) and frequently can miss smaller vegetations, myocardial abscesses, or other serious valvular abnormalities. 119 Patient and operator factors may affect the sensitivity of transthoracic echocardiography for detecting vegetations. Echocardiography should be considered in all cases of persistent Gram-positive cocci bacteremia more than 72 hours and is important not only for diagnosis, but for the detection of valvular dysfunction, assessment of hemodynamic severity, detection of shunts or abscesses, and serial evaluations of patients in complex situations (virulent organisms, severe hemodynamic compromise, persistent fever/ bacteremia, or clinical deterioration). In these cases, transesophageal echocardiography should be performed at least 5-7 days after the onset of bacteremia to decrease the risk of false-negative results. 9 Ultrasound and White Blood Cell Scans Ultrasonography of AV fistulas and grafts can be very useful in the setting of a clinically suspected infection to examine for local fluid collections or abscesses, as well as evaluate for thrombosis in the setting of bacteremia. 119 Use of radioisotope-tagged (either gadolinium or indium) white blood cells to localize sites of endovascular infection has potential utility in specific, but limited, clinical situations. In one comparison between computed tomography and gallium scintigraphy to diagnose endovascular graft infection, the sensitivity and specificity of computed tomography were 100% and 72% compared with 78% and 94% for gallium scintigraphy, respectively. 120 Accordingly, these tests are not considered first line for evaluation of bacteremia, but they may have a complementary role for localizing graft infections. Catheter Removal Hemodialysis patients with bacteremia present a unique challenge given the ongoing need for vascular access complicating removal of infected catheters and difficulty with peripheral venous access sites. 61 Treating a catheter-related bacteremia infection while salvaging a functional hemodialysis access catheter generally would be desirable; however, risks of progressive infection and sepsis, metastatic complications, and relapsing infection often outweigh the benefits of this approach. Evidence-based guidelines by the Infectious Disease Society of America (IDSA) for management of catheter-related bacteremia are both organism and situation specific, allowing for attempts at catheter salvage in certain circumstances. 9 For example, retention of an infected catheter can be considered in uncomplicated nonsustained BSIs with a low-grade pathogen, such as CoNS. In contrast, eradication of S aureus BSIs in the setting of an indwelling catheter generally is not achievable without removal of the catheter. Administration of antibiotics alone is not a satisfactory approach given the high risk of recurrence of S aureus in these patients. 16 The flow diagram in Fig 3 offers suggestions for catheter and antibiotic management based on the isolated Grampositive organism. Catheter removal is strongly recommended in the following circumstances: severe sepsis, hemodynamic instability, endocarditis, evidence of metastatic infection, or persistent bacteremia after 72 hours of antimicrobial therapy to which the pathogen is susceptible. Furthermore, when contemplating an attempt at catheter salvage, not only should the likelihood of cure be considered, but also the potential increased risk of complications or metastatic infection often associated with retention of an infected catheter should be carefully weighed and clinical management should be individualized. 9 Antibiotic Lock Therapy Antibiotic lock therapy has been a useful adjunctive treatment for the management of catheter-related bacteremia, with the goal of achieving supratherapeutic concentrations within the catheter lumen, thereby enhancing biofilm penetration to help eradicate organisms adhered to the device itself. 121 Antibiotic lock therapy in combination with systemic antimicrobials could facilitate catheter salvage in clinically stable patients when the BSI is due to low-virulence pathogens (ie, CoNS). Antibiotic lock therapy in conjunction with empiric systemic antibiotics is recommended in the 2009 IDSA guidelines in the initial management of suspected catheter-related bacteremia. 9 The ability to salvage a tunneled dialysis catheter using a combination of systemic antimicrobials and antibiotic lock therapy primarily is a function of the infecting organism, with reported success of 75%- 84% with CoNS compared with 61% with Enterococcus and only 40%-55% with S aureus

7 Fitzgibbons et al Figure 3. Flow diagram for managing Gram-positive cocci in hemodialysis (HD) patients with a central venous catheter (CVC). *Consider transesophageal echocardiography in HD patients with these infections within 5-7 days when possible; should be performed if bacteremia persists longer than 72 hours. Abbreviations: PCR, polymerase chain reaction; PNA FISH, peptide nucleic acid fluorescent in-situ hybridization; MIC, minimum inhibitory concentration; VRE, vancomycin-resistant enterrococci. Source: Mermel et al. 9 Antibiotic lock therapy usually involves the instillation of high-dose antibiotics at the completion of each dialysis session into the catheter to maintain high concentrations within the catheter. The antibiotic is prepared using either heparin or normal saline solution to achieve a goal concentration of at least 1,000 times higher than the minimum inhibitory concentration (MIC). 122,123 Commonly used antibiotic lock solutions are listed in Table 2, and the choice of antibiotic lock therapy should be individualized based on susceptibility testing of the cultured organism. The role of antibiotic lock therapy for prophylactic or pre-emptive empiric therapy has been studied in hemodialysis patients. Landry et al 128 showed that a prophylactic gentamicin-containing antibiotic lock solution decreased the rates of catheter-related bacteremia from 17 to 0.83 events/1,000 catheter-days. However, gentamicin-resistant bacteremia developed in this population, including gentamicin-resistant enterococcal infections, which were associated with significant morbidity and mortality. Rjinders et al 129 showed a benefit of antibiotic lock therapy over placebo with fewer relapses, but found barriers to its implementation because of lock times and the need for more broad-spectrum antibiotics. Doga et al 130 used gentamicin in citrate to prevent catheter-related bacteremia and found that it also significantly decreased infections, but was associated with increased serum gentamicin levels. For these reasons, antibiotic lock therapy is best reserved for adjunctive treatment to systemic antibiotics when catheter salvage is being attempted in the setting of an active BSI, as opposed to routine prophylaxis, to prevent the emergence of highly resistant pathogens in a hemodialysis unit. Surgical Assessment Surgical assessment should be considered for Grampositive cocci BSIs when there is persistence of infection or infection with an antibiotic-resistant organism, Table 2. Antibiotic Lock Solutions Used for the Treatment of Catheter-Related Bloodstream Infections Organism Antibiotic Comments Methicillin-resistant Staphylococcus aureus or coagulase-negative staphylococci Methicillin-sensitive S aureus or coagulasenegative staphylococci Enterococcus faecalis/faecium Vancomycin, mg/ml Cefazolin, 5 mg/ml Ampicillin, 10 mg/ml; vancomycin, 5 mg/ml Typical concentrations in 2- to 5-mg/mL range 9, Heparin or normal saline solution added to create lock solution Typical concentrations in 5- to 10-mg/mL range 9, Heparin or normal saline solution added to create lock solution Specific antibiotic should be based on susceptibilities Typical concentrations for ampicillin in 5- to 10- mg/ml range 9,127 Heparin or normal saline solution added to create lock solution 630

8 Gram-Positive Bacteremia and Hemodialysis such as MRSA and VRE, with limited effective antibiotic choices. Removal of the infected AV access, septic venous thrombi, and catheter tunnel infections may be surgical emergencies. Additionally, other infections, such as endocarditis, osteomyelitis, or deeptissue abscess, may need surgery to control infection or prevent mortality. 5,131 ANTIBIOTIC TREATMENT General Considerations Antibiotic treatment should be individualized in a patient with BSI, based on the susceptibility profile of the organism and with consideration of the increased risk of potential toxicities, as well as the feasibility of administration route and frequency of dosing required for a particular patient. These considerations are unique in the setting of hemodialysis because of vastly different pharmacokinetics of several of the commonly used antibiotics compared with patients with normal kidney function. The development of resistance on an individual level, as well as on a community level, is heavily influenced by net antibiotic use. As an example, prolonged exposure to vancomycin correlates with the development of hvisa. 10,132 Defining clear treatment goals, including the intended duration of antimicrobial therapy, will help minimize unnecessary drug exposure, decreasing the risk of resistance to the individual and the community. A summary of the agents and dosing is listed in Table 3. Specific Agents Ampicillin Ampicillin is used mostly to treat E faecalis BSIs in hemodialysis patients. Although vancomycin has obvious ease of dosing, it has a higher clinical failure rate in the treatment of E faecalis infection and can lead to the emergence of VRE. 11 Ampicillin is preferable to ampicillin/sulbactam, which may underdose the ampicillin component in hemodialysis patients. 142 Normal dosing would require 8-12 g of ampicillin daily in 4-6 divided doses. In hemodialysis patients, the dosage ranges from 1-2 g every hours. If dosed every 24 hours, the dose should be given daily, but after dialysis on dialysis days. 143 Nafcillin and Oxacillin Nafcillin and oxacillin are limited to the treatment of MSSA infections. Neither requires renal dosing adjustment for hemodialysis patients, but their use is limited because of the need for a separate intravenous (IV) catheter. 144 Cefazolin Cefazolin is the only parenteral first-generation cephalosporin. It has clinically useful activity against MSSA, but has no MRSA or enterococcal activity. 61 In hemodialysis patients, cefazolin has decreased excretion and prolonged half-life. Approximately 50%- 60% of drug is cleared by hemodialysis, and this is dependent somewhat on whether high-flux or highefficiency dialyzers are used. Recommended dosing is mg/kg after each hemodialysis session; this has been shown to maintain adequate serum concentrations through a 2- or 3-day interdialytic period regardless of dialyzer type. 145 An alternate standardized dosing schedule of cefazolin, 2 g, IV postdialysis if the next dialysis treatment is planned in 2 days and 3 g postdialysis if the next dialysis treatment is planned in 3 days also has been shown to be effective. 115 Vancomycin Vancomycin is a cell wall active glycopeptide and is the most commonly used systemic antibiotic in patients on hemodialysis therapy. 61 Vancomycin s spectrum of activity includes Gram-positive organisms; however, it is used primarily to treat MRSA infection because -lactam antibiotics provide superior treatment for MSSA and other common Grampositive infections. 115 The pharmacokinetics of vancomycin is favorable for dialysis patients because the drug is primarily renally excreted. The degree of nonrenal clearance is variable, but probably is 5% in the setting of normal kidney function. Serum halflife in dialysis patients, although invariably longer than in their counterparts with normal creatinine clearance, is a function of the dialyzer used. As dialysis technology has improved, including increased biocompatibility of membranes, larger surface area dialyzers, and higher permeability dialyzers, the dialysisassociated clearance of vancomycin has increased. In an anephric patient, the estimated serum half-life is 7.5 days, leading to previously recommended doses in the era of low-flux hemodialysis membranes of 15 mg/kg every 7-10 days. 146 In contrast, high-flux membranes are associated with greater vancomycin clearance and thus the need for more frequent dosing. 147 For patients undergoing hemodialysis using high-flux membranes, Barth and DeVincenzo 147 suggested a 20-mg/kg loading dose, followed by 500-mg supplementation after each dialysis session, which resulted in a mean trough level of 15.9 g/ml, whereas once-weekly dosing in this setting was associated with subtherapeutic trough levels. Although an alternate dosing schedule of a 1-g loading dose followed by 500 mg during the last hour of a high-flux hemodialysis session also has been proposed, this led to a lower mean trough level of g/ml. 148 With the emergence of hvisa, there is some suggestion that goal trough levels for patients with S aureus 631

9 632 Table 3. Recommended Antibiotic Dosing in Hemodialysis Patients With Gram-Positive Bacteremia Pathogen Type First-Line Therapy Second-Line Therapy Duration 9,124 Retention 9,124 Catheter Comments Methicillin sensitive Methicillin resistant Cefazolin,2gIVafter each HD session, 3 g IV if 2 d until next session (eg, if receiving HD on Mon, Wed, Fri, 2 g onmon,2gonwed,3gonfri) 115 Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a Staphylococcus aureus Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a Daptomycin, 6-8 mg/kg IV every 48 h (dosed every 48 h, but after HD on HD days) 134, d b No Vancomycin trough levels should be maintained at mg/l d b No Vancomycin trough levels should be maintained at mg/l 133 ; doses 6 mg/kg may be considered in some cases Monitoring parameters for daptomycin: check baseline CK & weekly thereafter 135,136 Methicillin sensitive Methicillin resistant Cefazolin,2gIVafter each HD session, 3 g IV if 2 days until next session (eg, if receiving HD on Mon, Wed, Fri, 2 g onmon,2gonwed,3gonfri) 115 Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a Coagulase-Negative Staphylococci Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a Daptomycin, 6-8 mg/kg IV every 48 h (dosed every 48 h, but after HD on HD days) 4, d if catheter retained and antibiotic lock therapy used d if catheter retained and antibiotic lock therapy used Yes, if uncomplicated Yes, if uncomplicated Vancomycin trough levels should be maintained at mg/l 3 ; consider daptomycin if vancomycin MIC 2 mg/ml E faecalis E faecium Vancomycin-sensitive E faecium Vancomycin-resistant E faecium d Ampicillin, 1-2 g IV every h 137 gentamicin c If ampicillin sensitive (rare), ampicillin, 1-2 g IV every h 137 gentamicin c Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a gentamicin c Daptomycin, 6-8 mg/kg IV every 48 h (dosed every 48 h, but after HD on HD days) 135,138 Enterococci Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a Daptomycin, 6-8 mg/kg IV every 48 h (dosed every 48 h, but after HD on HD days) 135,138 Vancomycin, 25- to 30-mg/kg IV loading dose (not 2 g), then as needed after HD based on levels a gentamicin c Daptomycin, 6-8 mg/kg IV every 48 h (dosed every 48 h, but after HD on HD days) 135,138 Linezolid, 600 mg every 12 h 139,140 Quinupristin-dalfopristin 7.5 mg/kg IV every 8 h d No Ampicillin is preferred over other antibiotics if isolate is susceptible Vancomycin trough levels should be maintained at mg/l d No d d No Linezolid toxicity accumulates in HD patients; need weekly CBC; monitor for neurotoxicity; avoid with serotonin agonist drugs 139,140 Daily monitoring: arthralgias & myalgias common, drug-drug interactions (inhibits cytochrome P450 3A4 enzymes), hyperbilirubinemia 139 Abbreviations: CBC, complete blood count; CK, creatine kinase; E, Enterococcus; HD, hemodialysis; IV, intravenous; MIC, minimum inhibitory concentration. a Vancomycin maintenance doses typically range from 500 mg to 1 g with each session and should be determined by periodic serum vancomycin levels drawn before the dialysis session. 133,141 b The 21-day duration is determined from the last positive blood culture and having negative transesophageal echocardiogram findings. c Gentamicin may be considered in synergy with either ampicillin or vancomycin when there is no bacteremia clearance within 72 hours or concern for endocarditis. d Vancomycin-resistant E faecium usually also has high-level aminoglycoside resistance. Fitzgibbons et al

10 Gram-Positive Bacteremia and Hemodialysis BSIs treated using vancomycin should be g/ml, 133,149 and 20 mg/kg (actual weight rounded to the nearest 250 mg) of vancomycin infused at 1,000 mg/h, timed to end with the dialysis session, with subsequent doses of 1,000 mg of vancomycin during the final hour of each subsequent dialysis session performed reasonably well at achieving these levels. 150 Daptomycin Daptomycin is a cyclic lipopeptide antibiotic that exerts its bacteriocidal activity through depolarization of the bacterial cell membrane, and its activity is restricted to Gram-positive bacteria. It is dosed by patient weight and dosing intervals are dependent on kidney function, with 78% of this drug excreted unchanged in urine. The recommended dose for BSIs is 6 mg/kg every 48 hours on hemodialysis, or more practically after each hemodialysis if this is 3 times a week. 151,152 Weekly measurement of creatine kinase is recommended, with additional assessment in the setting of myopathy symptoms (which are reversible on discontinuation). 136 Tigecycline Tigecycline is a glycylcycline antibiotic that inhibits protein synthesis. It is a derivative of minocycline and has bacteriostatic activity against S aureus, including MRSA and E faecalis, as well as certain Gramnegative bacteria. 153 Dosing of tigecycline is not affected by kidney function; therefore, dosing is 100 mg IV as an initial loading dose followed by 50 mg twice daily regardless of kidney function. 154 Of concern is that the antibiotic does not achieve very high serum levels, which may limit its utility for Grampositive cocci BSI. 154 Quinupristin-Dalfopristin Quinupristin-dalfopristin is a coformulated streptogrammin antibiotic that uses synergy to inhibit bacterial protein synthesis. 155 The recommended adult dosage is 7.5 mg/kg 3 times a day, and because of its fecal excretion, there is no dose adjustment necessary for patients on hemodialysis therapy. Despite having activity against E faecium and MRSA, it has no activity against E faecalis. 139 Its clinical utility is limited by adverse effects, most prominently myalgias, arthralgias, nausea, and abnormal liver function test results. 139 Its use in hemodialysis patients is limited by its dosing frequency and need for another central catheter access. Linezolid Linezolid is an oxazolidinone antibiotic that targets the ribosome of Gram-positive cocci. 139 Linezolid has nearly complete oral bioavailability and is used for short-term treatment of skin and soft-tissue infections or hospital-acquired pneumonia. Its utility in BSI is limited by its bacteriostatic properties, as well as significant myelotoxicity and neurotoxicity associated with long-term use. 139 These adverse effects may be potentiated in patients on hemodialysis therapy. 140 TREATMENT OF SPECIFIC INFECTIONS General Considerations for S aureus Bacteremia The optimal approach to patients with S aureus BSI and a hemodialysis catheter involves catheter removal and a temporary replacement immediately before the next required hemodialysis session if the BSI has not cleared. The alternative approach involves changing the catheter over a wire until more permanent access can be obtained, with the caveat that this strategy is associated with increased treatment failure. 9 Daily blood cultures documenting clearance of bacteremia should be performed and be clear for 48 hours before placing a new permanent catheter. 9 Methicillin-Sensitive S aureus Use of parenteral -lactam antibiotics is preferred over vancomycin for the treatment of MSSA BSIs because -lactam antibiotics are bactericidal in vitro and have improved clinical outcomes. 156 When Stryjewski et al 115 compared vancomycin and cefazolin treatment for MSSA BSIs in hemodialysis patients, clinical failure rates were 31.2% and 13%, respectively (P 0.02). Although other -lactams can be used, cefazolin is easily dosed, does not require additional venous access, and has good efficacy for the treatment of MSSA BSIs. 157 Therapy length typically is 3 weeks after the last positive blood culture result, although often longer in the setting of endocarditis. 9 Methicillin-Resistant S aureus When MRSA bacteremia has been identified, the initial management should include determination of the vancomycin MIC. Although vancomycin is the preferred treatment for MRSA BSIs in dialysis patients, delayed bloodstream clearance of MRSA bacteremia should raise concern for an hvisa strain. 9,27,115,149,158 Infusion reactions (ie, red-man syndrome ), which often are mistaken for vancomycin allergy, usually can be overcome by slowing the rate of infusion and/or administering an antihistamine. Daptomycin can be considered an alternative therapy if vancomycin cannot be used. 137 Daptomycin susceptibility testing should be performed if it is being used for an hvisa BSI in a hemodialysis patient because there is potential for the development of daptomycin nonsusceptibility during the treatment 633

11 Fitzgibbons et al course. 159 The recommended duration of therapy is similar to that for MSSA ( 3 weeks after the last positive blood culture result in the absence of endocarditis). 9 The role of aminoglycoside synergy with a -lactam for S aureus BSIs has been questioned in patients without kidney disease. 136,160 Although Korzeniowski and Sande 161 showed that the addition of an aminoglycoside to nafcillin significantly decreased S aureus bacteremia duration from 4.3 to 2.8 days, there was no impact on mortality, and aminoglycoside use was associated with increased nephrotoxicity. Fowler et al 136 also showed significantly more nephrotoxicity (26% vs 11%; P 0.004) in the aminoglycoside group without an effect on mortality. In hemodialysis patients, the benefits of aminoglycoside synergy with a -lactam to decrease bacteremia duration and cover suspected Gram-negative infections are such that aminoglycosides should be used as long as treatment is discontinued immediately after either resolution of the MSSA bacteremia and/or failure to show a Gram-negative organism. 107 Of note, aminoglycoside resistance is increasing in patients with MRSA bacteremia; thus, susceptibilities should be performed as needed. The addition of rifampin to vancomycin for MRSA bacteremia also is controversial. 162 Levine et al 163 showed no significant effect on bacteremia duration with combination therapy, whereas Riedel et al 164 showed that the addition of rifampin did not improve clinical outcomes and resulted in the emergence of rifampin-resistant S aureus isolates with associated serious drug interactions and hepatotoxicity. Accordingly, it is not recommended to add rifampin to vancomycin therapy for the treatment of S aureus BSI. 114 Linezolid should not be used routinely for MRSA BSIs. A phase 3 study using linezolid for BSIs showed that it was noninferior to vancomycin for CoNS BSIs, but with S aureus BSIs, the confidence intervals were outside the predetermined ranges for success. 165 In view of these data, linezolid could be reserved for short-term oral therapy until new access can be obtained. 9 Oral agents, such as clindamycin, trimethoprim-sulfamethoxazole, and tetracycline derivatives, generally should be avoided for MRSA BSI therapy because of their bacteriostatic pharmacokinetics and the rapid emergence of resistance. 166,167 Very few new antibiotics currently are in development. 168 Most recently, telavancin, a new lipoglycopeptide, was given US Food and Drug Administration approval for MRSA skin and soft-tissue infections. However, there are no BSI data to date. 169 Older antibiotics, such as quinupristin-dalfopristin, although effective, are limited by toxicities and the need for additional vascular access. Coagulase-Negative Staphylococci In general, management of CoNS can be through the present catheter, with removal if persistent bacteremia or other complications develop. Speciation of CoNS is performed uncommonly, and management has to rely on the susceptibility profile. Staphylococcus epidermidis is the most common species and frequently is methicillin resistant. Therefore, vancomycin is the usual first line of antimicrobial therapy. 14 Treatment through the hemodialysis catheter with systemic antibiotic and antibiotic lock therapy are recommended with this infection. 9 If the BSI does not clear with vancomycin treatment, the next steps should be to confirm the vancomycin MIC of the organism and consider catheter exchange over a wire. If the BSI does not resolve after these interventions or there is clinical instability, the catheter should be removed and investigation into an uncontrolled focus of infection should be initiated, with consideration of echocardiography and checking for other implanted hardware (pacemakers) or devices. 9 S lugdunensis, a generally methicillin-susceptible species of CoNS, has more invasive potential than other CoNS and should be considered with persistent bacteremia or a clinically aggressive CoNS infection. If there is suspicion for S lugdunensis, species-level identification should be requested and treatment with cefazolin should be considered. 170 The recommended length of therapy for uncomplicated CoNS catheter-related bacteremia is days if the catheter is retained and antibiotic lock therapy is used. 9 Enterococci Enterococcal BSIs are notoriously difficult to treat given the limited choice of effective antibiotics. The general principle for catheter management is the same as with S aureus infections, with catheter removal essential for VRE given the high relapse rate when catheters are retained. Penicillin and ampicillin are the preferred antimicrobials for treatment of susceptible enterococcal BSI. Use of ampicillin and aminoglycoside synergy with either low-dose gentamicin or streptomycin has been well shown in the treatment of E faecalis bacteremia. 171 The length of therapy usually is a minimum of 2 weeks after clearance and up to 6 weeks depending on associated complications. There are multiple antibiotic resistances associated with VRE infections, including aminoglycoside resistance. 55 There are few proven effective agents for VRE BSIs, with daptomycin or linezolid as the pri- 634