Chapter 49: Catheter-Related Bloodstream Infections

Positive microbiologic results of paired blood cultures drawn from the CVC and peripheral vein support the diagnosis of CRBSI, with particular emphasis on the differential time to positivity. CVC catheter tip cultures showing the same organism as found in the blood are also useful in identifying the line as the source of bloodstream infection.¹

The differential diagnosis for infections causing fever in the ICU setting is broad, and CRBSIs are the third most common infection diagnosed in the ICU, following pneumonia and sinusitis.² About 5% of patients with central venous catheters develop CRBSIs, and the incidence increases with the duration of catheter use and number of lumens.

Diagnosis of CRBSI includes both examination of the catheter site, looking for overt signs of infection such as purulence, erythema, or tenderness, and the use of blood cultures.³ Blood cultures must always be obtained before initiating antimicrobial therapy, one set from the catheter and one from a peripheral vein. The blood culture sets must be labeled with the source and time to assist in diagnosis. In CRBSI, the cultures drawn from the catheter will often become positive before the peripheral blood culture, reflecting the higher burden of organisms on the catheter.⁴

If there are signs of infection at the catheter insertion site or tenderness over the subcutaneous portion of the catheter, the catheter must be removed and the catheter tip submitted for quantitative culture. Positive catheter tip cultures are considered clinically significant when greater than 15 colony-forming units (cfu) of the same organism isolated from the blood culture are also isolated from the catheter tip.¹ Figure 49-1 delineates the initial approach to patients with CRBSI.

Catheters commonly used in ICU settings include both short-term and long-term catheters. Short-term catheters include peripheral intravenous (IV) lines, arterial lines, peripherally inserted central catheters (PICCs), and central venous catheters such as subclavian lines and pulmonary arterial catheters. Long-term catheters are surgically implanted lines including Hickman-type catheters and subcutaneous ports. In most cases of suspected CRBSI, short-term catheters are removed and the catheter tip sent for culture. Long-term catheters often require removal as well, particularly in cases of Staphylococcus aureus, Candida, and multidrug-resistant (MDR) infections.¹ Long-term catheters may be retained for treatment of coagulase-negative Staphylococcus species and Enterococcus species, unless there are overt signs of catheter-site infection or complicated infection such as endocarditis or osteomyelitis are present.

S aureus and Candida species are of particular concern. Other common pathogens are coagulase-negative Staphylococcus species and enteric gram-negative organisms, particularly MDR gram-negative rods.

Organisms identified with CRBSI in the ICU include coagulase-negative Staphylococcus species (36%), S aureus (17%), Candida species (10%), and Enterococcus species (10%). Enteric gram-negative organisms, including Escherichia coli, Klebsiella, Pseudomonas, and Enterobacter, collectively account for 15% to 20% of CRBSIs in the ICU.⁵

S aureus and Candida species are of particular concern because of the possibility of causing complicated bloodstream infection, including sepsis syndromes, endocarditis, and osteomyelitis. Candida species may cause endophthalmitis. Additional evaluation is warranted when S aureus and Candida are isolated to identify potential complications that will impact on the selection of the appropriate antimicrobial agent and duration of treatment. These evaluations may include the use of transesophageal echocardiography (TEE) to exclude endocarditis in patients with S aureus, venous Doppler ultrasound to evaluate for venous thrombosis, computed tomography to look for occult abscesses, and ophthalmologic examination to assess for endophthalmitis in the case of Candida infection.¹

Enteric gram-negative organisms are of concern in the ICU because of the increasing prevalence of MDR organisms, including extended-spectrum β-lactamase (ESBL)-producing organisms and carbapenemase-producing organisms, making selection of appropriate antibiotics for both empirical and directed therapy a challenge. Knowledge of one's local ICU epidemiology will assist in selecting appropriate empirical antimicrobial therapy, particularly the prevalence of methicillin-resistant S aureus (MRSA) and MDR gram-negative bacteria.

Common empirical regimens include an antibiotic effective for gram-positive organisms, including Staphylococcus species, such as vancomycin or daptomycin, with a broad-spectrum antibiotic for gram-negative organisms, such as a fourth-generation cephalosporin or an aminoglycoside.^{6, 7} Therapy is then tailored to the specific organism isolated from the blood cultures and the results of susceptibility testing.¹

β-Lactam antibiotics, such as nafcillin and cefazolin, are the preferred agents for MSSA. Alternative agents for penicillin-allergic patients include vancomycin and daptomycin.

MSSA is best treated with antistaphylococcal penicillins such as nafcillin or oxacillin. Cefazolin, a first-generation cephalosporin, is also effective.⁸ In vitro data suggest that β-lactam antibiotics are more bactericidal than alternatives.

For penicillin-allergic patients, clarifying the allergy history is important. For less severe or remote allergies such as skin rashes, the use of cefazolin is often tolerated, given the reported cross-reactivity of 10% to penicillins. Vancomycin and daptomycin may be used in the highly allergic patient, such as those with a history suggestive of immediate hypersensitivity reactions, such as hives; tongue, lip, or facial swelling; and shortness of breath. Higher failure rates are reported with vancomycin.⁹ For highly allergic individuals, consultation with an allergist is helpful to obtain skin testing and provide desensitization to the β-lactam antibiotic when indicated for complicated infections with MSSA.

In addition to β-lactam allergies, clinicians need to be aware that β-lactam antimicrobials also lower the seizure threshold. This patient with seizure activity reported on presentation must be monitored closely for the precipitation of seizures.

For MRSA, vancomycin or daptomycin are effective. Daptomycin is preferred when the minimum inhibitory concentration (MIC) to vancomycin is greater than 2 μg/mL.¹ Linezolid appears less effective for MRSA bloodstream infections, and resistance has been reported.¹ Table 49-1 delineates preferred and alternate antimicrobial therapies for MSSA, MRSA, and other gram-positive organisms.

Follow-up blood cultures to document clearance of infection and additional testing to eliminate the possibility of endocarditis, which would lengthen the antimicrobial course, should be done. In cases of persistent fever or hypotension, repeated blood cultures are essential both to ensure the current infection is adequately treated and to eliminate the possibility of new pathogens. Figure 49-2 outlines the approach to S aureus CRBSI.

Follow-up blood cultures should be drawn after the patient is started on antimicrobial therapy to confirm clearance of the organisms and establish the start date for the antimicrobial course. In all cases of S aureus CRBSI, the catheter should be removed if not done on the first day. If follow-up cultures are positive or if fever persists, further testing to evaluate for endovascular or metastatic foci of infection must be performed. This would include TEE to evaluate the endocardium and rule out endocarditis, venous ultrasounds to rule out venous thrombophlebitis, or computed tomography of the abdomen to look for occult abscesses and other sites of infection.

In cases of S aureus CRBSI, a minimum of 4 weeks of antimicrobial therapy is indicated, unless signs and symptoms resolve quickly after the initiation of antibiotics and line removal, there is no evidence of complicated infection, and the patient does not have diabetes or immunocompromise elevating the risk for complications. A negative TEE is essential if a 2-week course of antibiotics is considered.¹

Four weeks of antimicrobial therapy is generally indicated in cases of S aureus CRBSI.¹⁰ The antibiotic course is extended to 6 weeks or longer for patients with complicated bloodstream infections, prolonged periods of bacteremia, endocarditis, or other sites of infection. The duration of therapy is counted from the date when follow-up blood cultures have documented sterility.

A 14-day course may be considered in patients who defervesce quickly with therapy and catheter removal, and whose follow-up blood cultures are negative and who do not have signs or symptoms of complicated infections such as endocarditis or thrombophlebitis. Patients with diabetes, immunocompromised states, or permanent intravascular devices such as pacemakers are excluded from short-course therapy.¹¹

In cases where the patient is found to have a catheter tip colonized with S aureus with negative blood cultures, a very short (5- to 7-day) course of antibiotics is warranted to ensure more complicated infection does not result.¹²

The PICC line was removed promptly, and the tip was sent for culture. Intravenous caspofungin was started (70-mg loading dose, then 50 mg daily), and repeat blood cultures were drawn. A dilated funduscopic examination was performed; endophthalmitis was not detected.

Candida ranks fourth as a cause of nosocomial bloodstream infections in the United States, and third in the ICU.⁵ Risk factors for candidemia include the following: use of broad-spectrum antibiotics, parenteral nutrition, or immunosuppressive agents; neutropenia; bone marrow or solid organ transplantation; major abdominal surgery; femoral catheterization; or colonization with Candida at multiple anatomic sites.^{1, 13} Common species that are recovered, in order of frequency, are C albicans, C glabrata, C parapsilosis, C tropicalis, and C krusei.¹⁴ Speciation and, in some cases, susceptibility testing are important for determining which antifungal treatment is optimal. Three major classes of antifungal therapy are commonly used. The triazoles, which include fluconazole, voriconazole, and posaconazole, have excellent efficacy against C albicans, C parapsilosis, and C tropicalis, but less predictable activity against C glabrata, and fluconazole has no activity against C krusei.¹⁵ Because of its excellent oral bioavailability and ease of dosing, fluconazole is the agent of choice for C albicans, C parapsilosis, and C tropicalis. The echinocandins, which include anidulafungin, caspofungin, and micafungin, are efficacious in treating almost all Candida species. The echinocandins have been shown to have decreased in vitro activity against C parapsilosis, and are not recommended as primary therapy for infection with this organism. However, clinical studies have not shown a significant failure rate with use of echinocandins in C parapsilosis candidemia. Thus, patients started empirically on an echinocandin can complete a treatment course with this agent in the setting of C parapsilosis infection if they show an appropriate clinical response to therapy.¹³ Advantages of echinocandins include once-daily dosing and few drug interactions; however, echinocandins can only be administered intravenously.¹⁶ Finally, amphotericin B preparations are also effective in treating most Candida species. However, given the increased rates of side effects and drug toxicity, use of amphotericin B preparations should be limited to resource-limited environments or specific situations, such as central nervous system or endovascular disease.¹³ Specific antifungal therapies and dosing for commonly encountered Candida species are listed in Table 49-1.

In patients with presumptive candidemia, prompt initiation of an antifungal agent is crucial.¹⁷ In cases where there is evidence for moderate to severe disease, hemodynamic instability, or recent azole use, an echinocandin is the recommended initial empiric therapy.¹³ For patients with presumptive candidemia but with less severe illness and no recent azole exposure, fluconazole may be utilized as initial therapy. This particular patient did show signs of hemodynamic instability; as such, initiation of an echinocandin was appropriate.

Similar to S aureus CRBSI, prompt removal of indwelling catheters should be performed in patients with candidemia. This is because of the higher rates of failure, longer duration of therapy, and increased mortality rate associated with catheter retention.^{18, 19} Once the catheter is removed, the tip should be sent for microbiologic evaluation to confirm catheter-related infection. After catheter removal and initiation of antifungal therapy, repeat blood cultures need to be done to document clearance of fungemia. Given the increased risk of endophthalmitis associated with candidemia and the potentially devastating consequences of this complication, patients should have a dilated funduscopic examination within a week of fungemia.¹³ This has important implications for duration of treatment and therapeutic choice, as well as possible need for surgical intervention.²⁰ Figure 49-3 illustrates the general approach to patients with CRBSI caused by Candida species.

If blood cultures reveal a Candida species that is susceptible to fluconazole, patients can be safely switched from the echinocandin to fluconazole.^{13, 21} Since the isolate was C albicans, transition from caspofungin to fluconazole is appropriate and cost-effective. Alternative agents can be considered if there are significant medication interactions with fluconazole, adverse events, or chronic conditions that increase the potential for adverse events such as end-stage liver disease and transaminitis. Duration of treatment in uncomplicated candidemia is 2 weeks from the time of the first negative blood culture.^{1, 13} If the patient has persistently positive blood cultures, an evaluation for metastatic foci of infection is needed; this would include a TEE to assess for infective endocarditis.

Although less commonly seen in patients, CRBSI due to gram-negative organisms is routinely encountered in the ICU setting. In hospitalized patients, infections due to highly virulent MDR organisms, such as Pseudomonas aeruginosa, ESBL-producing gram-negative bacteria, and Acinetobacter species, are becoming more prevalent.²² Empiric initiation of a broad-spectrum antibiotic that targets these gram-negative organisms is necessary, especially in patients who are critically ill and show signs of sepsis. Because bacteremia due to gram-negative organisms can be attributed to other causes, such as a urinary tract infection, pneumonia, or intra-abdominal abscess, assessing for other sources of infection is usually warranted. If the patient has a known history of colonization or infection with an MDR organism, targeted empiric therapy using two agents from different classes should be started.¹ Once the gram-negative organism is identified and susceptibilities are performed, antibiotic therapy can be narrowed to a single specific agent. Unlike S aureus and Candida species, gram-negative organisms tend not to cause metastatic foci of infection or endocarditis unless there is prosthetic material present; thus, further evaluation is indicated only if the patient has persistent bacteremia. Catheters can be salvaged if there is prompt response to antibiotic therapy; however, catheter removal is urged for highly virulent organisms such as P aeruginosa and MDR organisms.¹ Specific therapies and duration of treatment for select gram-negative organisms are listed in Table 49-1. Of note, carbapenems such as imipenem, meropenem, doripenem, and ertapenem are the antibiotics of choice for ESBL-producing organisms. Imipenem has the potential to lower seizure threshold and should be avoided in patients with risk factors for seizures.

Tunneled catheters and totally implantable ports are commonly used for patients who require long-term therapy. These catheters tend to have lower rates of bloodstream infection as compared to nontunneled catheters and may be kept in place for an extended period of time. Extraction of some of these catheters requires surgical intervention, which could create issues for patients with limited vascular access. Studies have shown that catheters can be salvaged with antibiotic-lock therapy and systemic antibiotics in select bloodstream infections.²³ Antibiotic-lock therapy consists of instilling an appropriate antibiotic solution in the lumen of the catheter while not in use, allowing the solution to dwell through the length of the catheter. Systemic antibiotics should be administered through the catheter, and the duration of treatment generally is about 2 weeks.¹ Removal of long-term catheters is indicated in patients who have persistent bacteremia despite 72 hours of appropriate antibiotic therapy, severe sepsis, tunnel infection, pocket infection, thrombophlebitis, or metastatic foci of infection. For S aureus, P aeruginosa, mycobacteria, or Candida CRBSI, removal of the catheter is strongly recommended. This is because of the increased risk of metastatic foci of infection that is associated with these organisms, which may lead to complications such as osteomyelitis, septic arthritis, and endovascular infection.^{10, 13} For this particular patient, removal of a long-term catheter would have been warranted for either infection.

Given the increased risk of morbidity and mortality, as well as excess hospital costs associated with CRBSI, prevention of these infections, particularly in the ICU, has become a priority in the health care setting. Implementing specific evidence-based interventions has been shown to be effective in decreasing the rates of infection; together, these interventions are commonly referred to as a "bundle."^{24, 25} The use of a checklist documenting appropriate steps is beneficial for ensuring proper catheter placement. Prior to catheter insertion, thorough hand hygiene should always be performed, as this has been shown to decrease rates of health care–associated infection.²⁶ Maximal barrier protection, including a mask, cap, sterile gloves, and gown, should be used, and a full-body sterile drape that completely covers the patient should be placed to minimize contamination.²⁷ Chlorhexidine-containing solutions have been shown to be more effective in preventing infection than povidone-iodine, and should be used routinely for sterilization of the skin prior to catheter insertion.²⁸ If there is a contraindication to using chlorhexidine, povidone-iodine can be used; however, povidone-iodine requires 2 minutes to dry before its antiseptic properties are in effect. One study also showed a decrease in CRBSI when ICU patients were bathed daily with a 2% chlorhexidine-impregnated washcloth.²⁹ In terms of types of catheters, both antimicrobial- and antiseptic-impregnated catheters have been shown to decrease infection rates, a consideration when CRBSI rates are high, despite all other appropriate measures.³⁰ Use of topical antibiotic ointments at insertion sites is not recommended, as this may encourage MDR bacteria and/or fungal colonization and risk of invasive disease. Location of catheter placement also influences risk of infection. Higher rates of infection are associated with jugular and femoral veins versus subclavian vein cannulation; likewise, lower extremity sites (ie, femoral) have increased risk versus upper extremity sites.³¹ A multicenter prospective study demonstrated that implementation of these preventative measures yielded a significant decrease in CRBSI in the ICU by as much as 66%.²⁴ Indwelling catheters should be removed promptly when they are no longer needed, and routine replacement of catheters should not be done unless there is concern for active infection.