Critical Care Medicine

Intravascular catheter and device-related infections

Catheter-related bloodstream infections (CRBSI)

Synonyms

Central-line associated bloodstream infection (CLABSI), catheter-associated bloodstream infection (CABSI)

Related condition

Bacteremia

1. Description of the problem

What every clinician needs to know

Vascular catheter use is a fundamental aspect of medical care in the United States, particularly in the critical care setting. Infection of indwelling catheters results in significant additional financial costs, increased length of hospital stays and significant patient morbidity. Most catheter-related bloodstream infections begin at the insertion site or the catheter hub. Catheters that have been in place for less than 7 days are more likely to have the insertion site as the source, whereas catheters in place for more than 7 days are likely to have the hub as the source.

Common organisms in order of prevalence are coagulase negative staphylococci, S. aureus, Candida species, and Gram negative bacilli. Initial management of suspected catheter-related infection requires decisions on retention or removal of the catheter and choice of empiric antibiotic therapy. Management should then be tailored based on the specific pathogen isolated.

Clinical features

  • Bacteremia/fungemia in a patient with a central venous catheter in place, clinical signs and symptoms of infection (fever, chills, hypotension) and no other alternative source of infection.

  • Clinical findings are generally unreliable because of poor sensitivity and specificity.

  • Most sensitive finding is fever, which has poor specificity.

  • Inflammation or purulence at insertion site has better specificity but is not sensitive.

  • Positive blood cultures in the absence of another source of infection should increase suspicion for CRBSI.

  • Clinical improvement after catheter removal is suggestive of CRBSI.

Clinical findings consistent with infection and at least one of the following three diagnostic criteria should be met:

  1. CVC tip and peripheral blood culture grow the same organism; catheter tip culture should be greater than15 colony forming units (cfu) by roll-plate method or greater than 102 cfu per catheter segment by quantitative methods.

  2. Blood drawn from the catheter lumen and blood drawn from a peripheral vein (or less optimally blood drawn from a different lumen) grows the same organism. Organisms from the infected catheter are present at three times the amount of the peripheral specimen based on quantitative culture methods.

  3. Blood drawn simultaneously from a catheter lumen and a peripheral vein (or less optimally a different catheter lumen) grow the same organism. Growth from the infected catheter is detected (by automated detection systems) at least 2 hours before growth of the peripheral vein or other catheter lumen specimen.

Key management points

  1. Empiric therapy should be started in any ICU patient with signs and symptoms of infection and suspected CRBSI.

  2. Empiric therapy should always include vancomycin (or daptomycin when vancomycin MIC>2 ug/ml) to cover MRSA until culture data are known.

  3. Empiric therapy for Gram negative organisms should be based on local antibiogram.

  4. Empiric combination therapy for multidrug-resistant organisms should be used when CRBSI is suspected in severely ill patients with sepsis, immunocompromised patients or patients colonized with resistant pathogens.

  5. Empiric therapy should include antifungal therapy for Candida species if the patient has risk factors including hemalotogic malignancy, stem cell transplantation, prolonged use of broad spectrum antibiotics, total parental nutrition, femoral catheterization or colonization with Candida species.

  6. Not all patients with clinically suspected CRBSI require immediate catheter removal. A number of studies have shown that a substantial portion of suspected CRBSI are ultimately found not to be catheter-related (PUBMED:17304454, PUBMED:14999442). Low risk patients (those patients who are immunocompetent, have no other intravascular foreign body, no signs of sepsis or shock, and no proven bacteremia or fungemia) can often be safely monitored without catheter removal while being assessed for possible CRBSI.

  7. Catheters should be removed from patients with CRBSI and any of the following clinical conditions: Severe sepsis; endocarditis; osteomyelitis; bacteremia or fungemia that persists for more than 72 hours despite appropriate therapy; tunnel infection; port abscess; infections due to S. aureau, P. aeruginosa, fungi or mycobacteria.

  8. In general, a short-term catheter should be removed if it is determined to be the source of infection. Long-term catheters that are the source of infection could be retained in special circumstances with close followup and the use of systemic antibiotics in combination with antibiotic lock therapy to salvage the catheter.

  9. In cases of CRBSI due to microbes that are frequently contaminants or difficult to eradicate (coagulase negative staphylococcus, Bacillus species, Micrococcus species, etc), catheters should be removed if there are multiple positive cultures with at least one positive blood culture from a peripheral vein.

General principles of catheter salvage therapy

Catheter salvage therapy is an attempt to eradicate infection by filling the infected lumen with supraphysiologic concentrations of antibiotics to which the organism is susceptible and allowing it to dwell for hours to days creating an antibiotic lock. This is used in combination with systemic therapy for a total of 10-14 days.

Decisions to attempt catheter salvage should be made in conjunction with an infectious diseases consultant. The decision is based on: (1) the need for the catheter; (2) the organism/organisms with high risk for metastatic complications such as Staphylococcus aureus and Candida species are poor candidates; 3) the patient/patients with high risk for complications, such as diabetic and immunocompromised patients, are poor candidates; 4) the length of time the catheter has been in place, which should be more than 2 weeks because the source of infection is likely to be the internal lumen of the catheter; 5) the logistics of allowing the antibiotics to dwell - catheters that are needed in the ICU are generally not good candidates for salvage therapy.

Catheter salvage therapy is used in patients with long term catheters who have limited venous access and need to retain the catheter. This occurs in individuals for whom the risk of removing the catheter (bleeding diathesis, lack of additional sites in which to place a new catheter) outweighs the benefit of leaving the catheter in place. The patient must not have signs or symptoms of an exit site infection, a tunnel infection, or any metastatic infection such as endocarditis or osteomyelitis.

2. Emergency Management

At least 2 sets of blood cultures should be obtained before starting broad spectrum antibiotics. Empiric therapy should include vancomycin (or daptomycin) and Gram negative coverage based on the local antibiogram. Antifungal coverage should be initiated for patients with hemalotogiic malignancy, stem cell transplantation, prolonged use of broad spectrum antibiotics, total parental nutrition, femoral catheterization or known colonization with Candida species. In patients who are unstable, the catheter should be removed.

3. Diagnosis

Diagnostic criteria and tests

Paired blood cultures should be obtained from a peripheral vein and the catheter. Bottles should be marked to reflect the site from which the blood came. If blood cannot be obtained from a peripheral vein, blood cultures should be obtained from different catheter lumens.

If the catheter is removed because of suspicion of infection, catheter tips should be sent for culture. Growth of more than 15 cfu by roll plate method or more than 102 cfu by quantitative broth culture reflects colonization. A colonized catheter with the same organism found in the blood culture is indicative of CRBSI.

A diagnosis of CRBSI requires that the same organism grow from at least one percutaneous blood culture and from the catheter tip. Alternatively, if the catheter is not removed, two blood cultures (one from the catheter and one from a peripheral vein) that meet criteria for differential time to positivity (DTP), or two blood cultures obtained from two different catheter lumens that meet DTP can be considered to reflect a CRBSI. If quantitative blood cultures are performed, a colony count of organisms grown from blood obtained through the catheter that is at least three times greater than the colony count obtained from a peripheral vein blood culture makes the diagnosis of CRBSI.

Confirming the diagnosis

The main diagnostic issue is matching blood culture to a catheter tip culture or obtaining blood cultures from the catheter lumens with a DTP greater than 2 hours.

Other possible diagnoses

If blood cultures and the catheter tip culture are negative, look for an alternative source of fever or consider mycobacterial infection.

4. Specific Treatment

Recommendations for specific treatment are based on the IDSA Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infections, PUBMED:19489710

Gram-positive cocci

Staphylococcus aureus:

Removal of the catheter is recommended, as it has been associated with more rapid clinical response and higher cure rates that retention of the catheter. S. aureus bacteremia results in hematogenous complications in 20-30% of patients, and failure or delay in removing the catheter increases this risk.

Specific therapy should be guided by susceptibility testing:

  • Methicillin-susceptible: Nafcillin or oxacillin 2 grams q 4 hours; alternatives are cefazolin 2 grams q 8 hours, or vancomycin 15mg/kg q12 hours; note that penicillinase resistant penicillins are preferred to vancomycin. If patient is allergic to penicillin, desensitization is preferred to vancomycin.

  • Methicillin-resistant: Vancomycin 15mg/kg q 12 hours; alternatives are daptomycin 6-8 mg/kg per day or linezolid 600 mg q 12 hours. Most patients should receive 4-6 weeks of therapy. Patients may be considered for a two week course of therapy if they have had the catheter removed, and they are not diabetic or immunocompromised by steroids or other immunosuppressive drugs. They also must have no other intravascular devices in place.

  • Fever and bacteremia must resolve within 72 hours of starting appropriate antimicrobial therapy, and there should be no signs or symptoms of metastatic infection on physical exam or diagnostic testing such as TEE to be considered for short-course therapy. If all of these criteria are met, patients could be considered for a 2 week course of therapy.

Coagulase-negative staphylococci:

Most patients with CRBSI due to coagulase-negative staphylococci have a fairly benign course. Removal of the catheter is generally recommended, combined with 5-7 days of therapy.

Specific therapy should be guided by susceptibility testing:

  • Methicillin-susceptible: Nafcillin or oxacillin 2 grams q 4 hours; alternatives are cefazolin 2 grams q 8 hours; vancomycin 15mg/kg q 12hours; or TMP/sulfa if susceptible.

  • Methicillin-resistant: Vancomycin 15mg/kg q 12 hours; alternatives are daptomycin 6-8 mg/kg per day or linezolid 600 mg q 12 hours.

  • Removal of short-term catheters is recommended.

  • Treat for 5-7 days.

  • If catheter salvage (see below) is attempted in long-term catheters, treat for 10-14 days.

Enterococcus:

Although the risk of endocarditis is relatively low with enterococcal bacteremia, prolonged bacteremia for more than 4 days is independently associated with mortality. For this reason, removal of short-term catheters is recommended.

Specific therapy should be guided by susceptibility testing:

  • Ampicillin/penicillin susceptible: Ampicillin 2 grams q 4 hours or q 6 hours +/- gentamicin 1 mg/ kg q 8 hours; alternative is vancomycin 15mg/kg q 12 hours.

  • Ampicillin resistant and vancomycin susceptible: Vancomycin 15mg/kg q 12 hours +/- gentamicin 1 mg/ kg q 8 hours. Target trough for vancomycin 20 mcg/ml; alternatives are daptomycin 6-8 mg/kg per day, or linezolid 600 mg q 12 hours, or quiniprstin/dalfopristin 7.5 mg/kg q 8 hours; note that quinipristin/dafolpristin is not effective against E. faecalis.

  • Ampicillin resistant and vancomycin resistant (VRE): linezolid 600 mg q 12 hours or daptomycin 6-8 mg/kg per day; alternative is quiniprstin/dalfopristin 7.5 mg/kg q 8 hours; note that quinipristin/dafolpristin is not effective against E. faecalis.

  • Treat for 10-14 days.

  • Data regarding combination therapy with an aminoglycoside are mixed. Retrospective observational studies have shown no difference in outcomes in uncomplicated enterococcal bacteremia with monotherapy compared to combination therapy. If the catheter is retained, however, combination therapy is recommended.

  • If catheter salvage is attempted in long-term catheters, treat for 10-14 days.

Gram-negative bacilli

Because many Gram negative bacilli form biofilms, most experts have advocated the removal of a bacilli-infected catheter. However, more recent studies examining the role of combination therapy for catheter retention have found some success. Removal of short-term catheters is generally recommended. Specific therapy should be guided by susceptibility testing.

E. coli and Klebsiella:

  • ESBL negative: ceftriaxone 1-2 grams q 24 hours or other 3rd or 4th generation cephalosporin; alternatives are ciprofloxacin 400 mg q 12 hours; levofloxacin 500 mg q 24 hours; moxifloxacin 400 mg q 24 hours; imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; doripenem 500 mg q 8 hours; or pipericillin/tazobactam 3.75 mg q 6 hours.

  • ESBL positive: imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; doripenem 500 mg q 8 hours +/- gentamicin; or tobramycin 5mg/kg q 24 hours; alternatives are ciprofloxacin 400 mg q 12 hours; levofloxacin 500 mg q 24 hours or moxifloxacin 400 mg q 24 hours. Note that quinolone resistance is rising; quinolones should not be used as empiric monotherapy. Removal of the catheter is recommended.

EnterobacterandSerratia marcescens:

Imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; doripenem 500 mg q 8 hour+/- gentamicin; or tobramycin 5mg/kg q 24 hours until susceptibility is known. Alternatives are ciprofloxacin 400 mg q 12 hours; levofloxacin 500 mg q 24 hours; moxifloxacin 400 mg q 24 hours or cefipime 2 grams q 8 hours. Removal of the catheter is recommended.

Pseudomonas aeruginosa:

Imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; doripenem 500 mg q 8 hour; piperacillin/tazobactam 4.5 grams q 4; cefipime 2 grams q 8 hours; ceftazadime 2 grams q 8 hours +/- tobramycin 5mg/kg q 24 hours; or amikacin 15mg/kg q 24 hours until susceptibility known; alternatives colistin 2.5 mg/kg q 12 hours; or polymixin 1.25 mg/kg q 12 hours. Removal of the catheter is recommended.

Acinetobacter:

Imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; or ampicillin/sulbactam 3 grams q 6 hours; alternatives are colistin 2.5 mg/kg q 12 hours; amikacin 7.5 mg/kg q 12 hours; or tigecycline 100 mg first dose then 50 mg q 12 hours. Removal of the catheter is recommended.

Stenotrophomonas maltophilia

TMP/sulfa 3-5 mg/kg q 8 hours; alternatives ticarcillin/clavulanate 3.1 g q 4 hours; ceftazadime 2 grams q 8 hours; or tigecycline 100 mg first dose then 50 mg q 12 hours. Removal of the catheter is recommended.

Burkholderia cepacia:

TMP/sulfa 3-5 mg/kg q 8 hours; imipenem 500 mg q 6 hours; meripenem 1 gram q 8 hours; or doripenem 500 mg q 8 hour; alternatives are ceftazadime 2 grams q 8 hours or minocycline 100 mg q 12 hours. Duration of therapy should be 10-14 days for Gram negative infections. Catheter salvage is not recommended for patients with multi-drug resistant organisms. For pan-sensitive Gram negative organisms, salvage therapy could be attempted in patients with long-term catheters. Treatment should be 10-14 days.

Fungi

In the setting of Candidemia with the catheter being the source, the catheter should be removed. Specific therapy should begin with an echinocandin.

Candida species:

Caspofungin 70 mg load then 50 mg q 24 hours; micafungin 100 mg q 24 hours; or anidulafungin 200 mg load then 100 mg q 24 hours; alternatives are fluconazole 400-600 mg q 24 hours (only in patients without prior azole exposure or if susceptibility is known) or liposomal amphotericin 5 mg/kg q 24 hours. Note that echinocandins should be used until fungal isolate is identified. All patients with candidemia should have ophthalmologic exam to rule out endophthalmitis. Removal of the catheter is recommended. Duration of treatment is 14 days after the last positive culture and symptom resolution. Treat longer for complications such as endophthalmitis, septic arthritis, osteomylelitis or endocarditis.

Refractory cases

Repeatedly positive blood cultures 72 hours after the catheter has been removed suggests serious complications of CRBSI such as endocarditis, osteomyelitis, thrombophlebitis or other metastatic site of infection. TEE should be done in any patient with persistently positive blood cultures 72 hours after catheter removal.

Risk of nosocomial endocarditis is highest in patients who have prosthetic heart valves, known valvular disease, pacemakers or AICDs, malignancies, or are receiving dialysis through a catheter. Organisms most likely to cause complicated infections are Staphylococcus aureas and Candida species. Endocarditis cannot be ruled out with TTE alone. TEE is most sensitive at least 5-7 days after the onset of bacteremia.

Patients with suspicion of suppurative thrombophlebitis should undergo radiographic imaging (CT scan, ultrasound or other imaging) to search for an infected thrombus. Patients with suspicion of osteomyelitis should undergo radiographic imaging (CT scan, MRI) to search for infected bony structure.

Surgical intervention may be required for patients with endocarditis, suppurative thrombophlebitis or osteomyelitis.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Blood cultures should clear and patient should become afebrile within 48 hours of starting appropriate therapy and removing the catheter.

Incorrect diagnosis

If blood cultures are persistently positive and/or the patient has persistent fever or other symptoms in the face of a negative catheter culture, consider other sources of infections.

Follow-up

Patients should have followup blood cultures drawn 24 hours after starting appropriate therapy.

Pathophysiology

There are four recognized routes of contamination of catheters:

  1. Migration of common skin organism at the insertion site down the cutaneous catheter tract and along the external surface of the catheter eventually colonizing the catheter tip. This is the most common route of infection for catheters that are infected fewer than 7 days after placement.

  2. Contamination of the catheter hub or catheter connectors by contact with contaminated hands, fluids or surfaces. This is the most common route of infection for catheters in place longer than 7 days due to the frequent accessing of multiple lumens.

  3. Hematogenous seeding of catheters from another source of infection.

  4. Contamination of infusate (much less common).

Important pathogenic characteristics of catheter infection:

  1. Host factors, which consist of protein adhesions such as fibrin and fibronectin, that form a sheath around the catheter.

  2. Intrinsic virulence factors on infecting organisms, including the extracellular polymeric substance produced by adherent organisms.

  3. The material from which the catheter is made.

Some catheter materials also have surface irregularities that enhance organism adherence. Catheters made from these materials are especially prone to colonization and infection. For example, after the formation of the fibrin sheath, catheters made from silastic are more vulnerable to infections than catheters made from polyurethane. Likewise, silicone catheters are more vulnerable to biofilm formation than polyurethane catheters. Additionally, some catheter materials are more thrombogenic than others. This may predispose the catheter to colonization and subsequent infection.

The adherence characteristics of microorganisms in relationship to host factors are also important in the pathogenesis of infection. Some organisms can adhere to host proteins commonly present on catheters by expression clumping factors that bind to protein adhesins. Adherence is then enhanced through the production of an extracellular polymeric substance consisting mostly of an exopolysaccharide that forms a microbial biofilm.

This biofilm is enriched by metallic cations such as calcium, magnesium, or iron which make it a hospitable environment for organisms to embed themselves. In the presence of catheters, this biofilm enhances the pathogenicity of some organisms by allowing them to tolerate host defense mechanisms (creating a physical barrier to polymorphonuclear cells) and making them less susceptible to antimicrobial agents (creating a barrier by forming a matrix that binds antimicrobial agents before they can come into contact with the organisms cell wall).

Epidemiology

Each year in the United States, hospitals and clinics purchase intravascular devices to administer intravenous fluids, medications, blood products and parenteral nutrition. In addition, intravascular catheters are used for hemodynamic monitoring and to provide hemodialysis. It is estimated that more than 300 million catheters are purchased each year, of which 3 million are central venous catheters.

Although significant gains in preventing infections have been made, CRBSI continue to occur with estimated rates ranging from 1.3/1000 catheter days on inpatient medical/surgical wards to 5.6/1000 catheter days in burn ICUs. Central venous catheters are usually classified as either long-term or short-term. Long term CVCs are surgically implanted or tunneled and used for prolonged chemotherapy, home-infusion therapy or dialysis. Short-term catheters do not require surgical implantation, are the most commonly used catheters and account for the majority of all CR-BSIs.

In order of prevalence, coagulase-negative staphylococci, Staphylococcus aureus, Candida species and enteric Gram negative bacilli account for the majority of infections. The frequency with which MRSA and resistant Gram negative bacilli are isolated in the ICU setting make it imperative to start broad spectrum empiric therapy to cover resistant organisms in ICU patients when susceptibility is unknown.

Prognosis

NA

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Mermel, LA, Allon, M, Bouza, E, Craven, DE, Flynn, P. "Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 50. 2010 Apr 1. pp. 1-45.

(This is the most recent comprehensive update in the diagnosis and management of CRBSI. The guideline reviews many scenerios for the care and management of both long- and short-term catheters.)

O’Grady, NP, Alexander, M, Burns, LA, Dellinger, EP, Garland, J. "Guidelines for the prevention intravascular catheter-related infections". Am J Infect Control. vol. 39. 2011 May. pp. S1-34.

(Comprehensive update on preventing catheter-related infections, including sections on pathophysiology of infection. This guideline also identifies several recommendations that can be incorporated into hospital-wide quality improvement programs.)

Bouza, E, Alvarado, N, Alcala, L, Perez, MJ, Rincon, C. "A randomized and prospective study of 3 procedures for the diagnosis of catheter-related bloodstream infection without catheter withdrawal". Clin Infect Dis. vol. 44. Mar 15 2007. pp. 820-6.

(This study details the procedures for diagnosing CRBSI, and also points out that not all cases of suspected CRBSI are confirmed.)

Rijnders, BJ, Peetermans, WE, Verwaest, C, Wilmer, A, Van Wijngaerden, E. "Watchful waiting versus immediate catheter removal in ICU patients with suspected catheter-related infection: a randomized trial". Intensive Care Med. vol. 30. Jun 2004. pp. 1073-80.

(This study points out that many catheters suspected of being a source of infection are often not the source. In addition, many can be carefully monitored without being immediately removed if the diagnosis is in question.)

Zinkernagel, AS, Zinkernagel, MS, Elzi, MV. "Significance of Staphylococcus lugdunensis bacteremia: report of 28 cases and review of the literature". Infection. vol. 36. Aug 2008. pp. 314-21.

(This review details the significance of Staphylococcus lugdunensis bacteremia.)

Malanoski, GJ, Samore, MH, Pefanis, A, Karchmer, AW. "Staphylococcus aureus catheter-associated bacteremia. Minimal effective therapy and unusual infectious complications associated with arterial sheath catheters". Arch Intern Med.. vol. 155. Jun 12 1995. pp. 1161-6.

(This publication outlines the difficulties associated with treating S. aureus bacteremia.)

Fowler, VG, Justice, A, Moore, C. "Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus bacteremia". Clin Infect Dis. vol. 40. Mar 1 2005. pp. 695-703.

(This publication analyzes independent risk factors for developing complicated infection from S. aureus bacteremia.)

Fowler, VG, Sanders, LL, Sexton, DJ. "Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients". Clin Infect Dis. vol. 27. Sep 1998. pp. 478-86.

(This publication analyzes outcomes for patients developing complicated infection from S. aureus bacteremia.)

Abraham, J, Mansour, C, Veledar, E, Khan, B, Lerakis, S. "Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia". Am Heart J.. vol. 147. Mar 2004. pp. 536-9.

(This study shows that S aureus bacteremia is associated with high rates of endocarditis. MSSA bacteremia is associated with higher rates of endocarditis than MRSA. Community MSSA is the cause of most of the community endocarditis, whereas nosocomial MRSA is the cause of most of the MRSA endocarditis. Patients with S aureus bacteremia should be aggressively evaluated for endocarditis.)

Fowler, VG, Miro, JM, Hoen, B. "Staphylococcus aureus endocarditis: a consequence of medical progress". JAMA. vol. 293. Jun 22 2005. pp. 3012-21.

(The authors document the international emergence of health care-associated S aureus endocarditis and MRSA endocarditis and evaluate regional variation in patients with S aureus endocarditis.)

Fowler, VG, Olsen, MK, Corey, GR. "Clinical identifiers of complicated Staphylococcus aureus bacteremia". Arch Intern Med.. vol. 163. Sep 22 2003. pp. 2066-72.

(The authors systematically identify clinical variables that put patients at risk for complicated S. aureus bacteremia.)

Chang, FY, MacDonald, BB, Peacock, JE. "A prospective multicenter study of Staphylococcus aureus bacteremia: incidence of endocarditis, risk factors for mortality, and clinical impact of methicillin resistance". Medicine (Baltimore). vol. 82. Sep 2003. pp. 322-32.

(The authors systematically identify clinical variables that put patients at risk for complicated S. aureus bacteremia.)

DiazGranados, CA, Jernigan, JA. "Impact of vancomycin resistance on mortality among patients with neutropenia and enterococcal bloodstream infection". J Infect Dis. vol. 191. Feb 15 2005. pp. 588-95.

(The authors use a retrospective cohort study design to show that vancomycin resistance is associated with increased mortality in patients with neutropenia, possibly because of prolonged duration of bacteremia.)

Sandoe, JA, Witherden, IR, Au-Yeung, HK, Kite, P, Kerr, KG. "Enterococcal intravascular catheter-related bloodstream infection: management and outcome of 61 consecutive cases". J Antimicrob Chemother. vol. 50. Oct 2002. pp. 577-82.

(This study shows that enterococcal CRBSI can be treated successfully without CVC removal. The combination of a cell wall-acting antimicrobial with an aminoglycoside was the most effective regimen when the CVC remained in situ in this small group of patients. Although CVC removal was associated with a high cure rate, it did not guarantee treatment success.)

Fernandez-Hidalgo, N, Almirante, B, Calleja, R. "Antibiotic-lock therapy for long-term intravascular catheter-related bacteraemia: results of an open, non-comparative study". J Antimicrob Chemother. vol. 57. Jun 2006. pp. 1172-80.

(Antibiotic lock therapy combined with systemic antibiotics seems to be effective for treating CRBSI, especially in Gram-negative and coagulase negative Staphylococci. Episodes. S. aureus CRBSI had an elevated rate of therapeutic failure.)

Poole, CV, Carlton, D, Bimbo, L, Allon, M. "Treatment of catheter-related bacteraemia with an antibiotic lock protocol: effect of bacterial pathogen". Nephrol Dial Transplant. vol. 19. May 2004. pp. 1237-1244.

(This study shows that the clinical success of an antibiotic lock protocol in eradicating catheter-related bacteremia while salvaging the catheter is highly dependent on the bacterial pathogen.)

Kuse, ER, Chetchotisakd, P, da Cunha, CA. "Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial". Lancet. vol. 369. May 5 2007. pp. 1519-27.

(This study showed that micafungin was as effective as - and caused fewer adverse events than - liposomal amphotericin B as first-line treatment of candidemia and invasive candidosis.)

Reboli, AC, Rotstein, C, Pappas, PG. "Anidulafungin versus fluconazole for invasive candidiasis". N Engl J Med.. vol. 356. Jun 14 2007. pp. 2472-82.

(This study shows that anidulafungin was shown to be as effective as fluconazole in the treatment of invasive candidiasis.)
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