Infections due to Infusion Therapy

Nasia Safdar

Dennis G. Maki

Leonard A. Mermel

Reliable intravascular access for the administration of fluids and electrolytes, blood products, drugs, and nutritional support, and for hemodynamic monitoring is now one of the most essential features of modern medical care (Table 38.1). Each year in the United States, ~150 million intravascular devices are purchased by hospitals and clinics. The vast majority are peripheral venous catheters; however, >5 million central venous devices of various types are sold in the United States annually.

More than one-half of all epidemics of healthcare-associated bacteremia or candidemia reported in the world literature between 1965 and 1991 are derived from vascular access in some form (1,2). One-third to one-half of episodes of healthcare-associated endocarditis have been traced to infected intravascular catheters (3,4,5,6,7), and healthcare-associated intravascular device-related bloodstream infection (IVDR-BSI) is associated with a 12% to 28% attributable mortality (8,9,10,11). Yet, infusion therapy generally has an underappreciated potential for producing iatrogenic disease. For example, <50% of the intensive care units (ICUs) in the United Kingdom had a written policy concerning the care of central venous catheters (CVCs) after insertion (12).

Infusion-related BSI is too frequently unrecognized, in great measure because of its relative infrequency. The percentage of infusions identified as producing BSI is sufficiently low—<1% on the average—that an average physician or nurse is unlikely to encounter more than an occasional episode. But even a low incidence of infection applied to the estimated 30 million patients who receive infusion therapy in U.S. hospitals annually translates into an estimated 50,000 to 100,000 BSIs nationwide each year (1,2,13), with 55,000 due to CVCs in U.S. ICUs (14,15). Because neither the device nor the infusate is routinely cultured, the source of the BSI in a large proportion of episodes is never recognized.

IVDR-BSI is largely preventable. This premise forms the thesis for this review: the primary goal must not be simply to identify and treat these iatrogenic infections, but rather to prevent them. By critically scrutinizing existing knowledge of the pathogenesis and epidemiology of device-related infection—the reservoirs of healthcare-associated infection (HAI) pathogens and modes of transmission to patients’ infusions—rational and effective guidelines for prevention can be formulated (16).

SOURCES AND FORMS OF INFUSION-RELATED INFLAMMATION AND BLOODSTREAM INFECTION

There are three major sources of BSI associated with any intravascular device: (a) colonization of the cannula wound, (b) colonization of the cannula hub, or (c) contamination of the fluid (i.e., infusate) administered through the cannula. Cannulas, which cause most endemic IVDR-BSIs, produce BSI far more frequently than contaminated infusate, the source of most epidemics of infusion-associated BSI (1).

It is important to understand the different stages and forms of device-related inflammation or infection, which range from infusion phlebitis—usually unrelated to infection—to asymptomatic colonization of the intravascular device—usually by skin commensals with little intrinsic virulence—to overwhelming septic shock originating from an infected thrombus in a cannulated great central vein or from infusate heavily contaminated by gram-negative bacilli.

INFUSION PHLEBITIS

Infusion phlebitis, defined as inflammation of the cannulated vein—pain, erythema, tenderness, or an inflamed, palpable, thrombosed vein—is a frequent cause of pain and discomfort to the millions of patients who receive infusion therapy through peripheral intravenous (IV) cannulas each year in U.S. hospitals. Most investigators have concluded that infusion phlebitis is primarily a physicochemical phenomenon, and prospective studies have shown that the cannula material, length, and bore size; operator skill on insertion; the anatomic site of cannulation; the duration of cannulation; the frequency of dressing changes; the character of the infusate; and host factors such as patient age, Caucasian race, female gender, and the presence of underlying diseases significantly influence the risk of infusion phlebitis (Table 38.2).

In a prospective clinical study of 1,054 peripheral IV catheters, the Kaplan-Meier risk for phlebitis exceeded 50% by the fourth day after catheterization. IV antibiotics (relative risk [RR], 2.0), female gender (RR, 1.9), catheterization beyond 48 hours (RR, 1.8), and catheter material (polyether urethane [Vialon]; tetrafluoroethylene-hexafluoropropylene [Teflon]; RR, 0.7) were strong predictors of phlebitis in a Cox proportional hazards model (each, p < .003) (17). The best-fit model for severe phlebitis identified the same predictors plus catheter-related infection (RR, 6.2), phlebitis with the previous catheter (RR, 1.5), and anatomical site (hand:forearm, RR, 0.7; wrist:forearm, RR, 0.6).

Although not all studies have identified an association between phlebitis and catheter-related infection (18,19), this large, prospective study showed a strong statistical association, as have other studies (20,21,22,23,24). Phlebitis can also be produced by contaminated infusate. Patients with BSI from intrinsically contaminated fluid in a large, nationwide epidemic traced to the contaminated products of one U.S. manufacturer in 1970 to 1971 had a much higher incidence of phlebitis than patients receiving IV fluids who did not develop BSI (25).

TABLE 38.1 Applications of Infusion Therapy in the 2000s

Fluid and electrolyte replacement
Transfusion therapy
Blood products
Exchange transfusion
Plasmapheresis and apheresis
IV drug administration
Immediate circulatory access for critically ill patients
High blood and tissue levels
Drugs that cause tissue necrosis
Drugs that cause thrombolysis
Hemodialysis
Hemodynamic monitoring
Central venous catheters
Central venous pressure
Pulmonary artery Swan-Ganz catheters
Pulmonary artery pressure
Pulmonary artery occlusion (left atrial filling) pressure
Thermodilution cardiac output
Arterial catheters
Continuous arterial blood pressure
Total parenteral nutrition
Hyperalimentation (central venous catheters)
Peripheral parenteral nutrition (peripheral IV catheters)
Special nutritional support regimens for:
	Acute renal failure
	Hepatic failure
	Cardiac cachexia
	Pancreatitis
	Acquired immunodeficiency syndrome
	Intra-arterial cancer chemotherapy
IV, intravenous.

Only a small proportion of patients with IV cannula-associated peripheral vein phlebitis have infusion-related infection, and <50% of patients with peripheral IVDR-BSI show phlebitis; however, the presence of phlebitis connotes a substantially increased risk of infection and indicates the need for immediate removal of the catheter to reduce the severity of phlebitis, for symptomatic relief, and to prevent catheter colonization from progressing to BSI.

CANNULA-RELATED INFECTIONS

Between 5% and 25% of intravascular devices are colonized by skin organisms at the time of removal, as reflected by semi-quantitative or quantitative cultures showing large numbers of organisms on the intravascular portion of the removed catheter or its tip. Colonization, which in most instances is asymptomatic, provides the biologic setting for systemic infection to occur and can be considered synonymous with localized infection. However, colonized cannulas are more likely than noncolonized ones to show phlebitis or local inflammation, especially purulence—pus spontaneously draining or expressible from the insertion site—and are far more likely to cause systemic infection (i.e., cannula-related bacteremia or fungemia) (21,26,27).

One of the most serious forms of intravascular device-related infection occurs when intravascular thrombus surrounding the cannula becomes infected. This causes septic (suppurative)
thrombophlebitis when it occurs in association with peripheral IV cannulas (28,29), or septic thrombosis of a great central vein when associated with centrally placed catheters (30,31). With suppurative phlebitis, the vein becomes an intravascular abscess, discharging myriads of microorganisms into the bloodstream, even after the cannula has been removed. The clinical picture is predictable: overwhelming BSI with high-grade and often unremitting bacteremia or fungemia. This syndrome is most likely to be encountered in burned patients or other ICU patients who have heavy cutaneous colonization and develop a cannula-related infection that goes unrecognized, permitting microorganisms to proliferate to high levels within the intravascular thrombus. The catheter insertion site is devoid of signs of inflammation >50% of the time, and the clinical picture may not present until several days after the catheter has been removed. In any patient with an IV catheter who develops high-grade BSI that persists after an infected cannula has been removed, it is likely the patient has an infected thrombus in the recently cannulated vein, and may even have secondary endocarditis or seeding to other distant sites (32).

TABLE 38.2 Risk Factors for Infusion Phlebitis in Peripheral IV Therapy Identified in Prospective Studies by Multivariate Discriminant Analysis or in Prospective, Randomized, Controlled Trial^a

Catheter material
	Polypropylene vs. Teflon
	Silicone elastomer vs. polyurethane
	Teflon vs. polyether urethane
	Teflon vs. steel needles
Catheter size
	Large bore vs. smaller bore
	8 vs. 2 inches Teflon
Insertion in emergency room vs. inpatient units
Disinfection of skin with antiseptic before catheter insertion
Experience and skill of the person inserting the catheter
	House officers, nurses vs. hospital IV Team
	House officers, nurses vs. decentralized unit IV nurse educator
Increasing the duration of catheter placement in site
Subsequent catheters beyond the first infusate
	Low-pH solutions (e.g., dextrose-containing)
	Potassium chloride
	Hypertonic glucose, amino acids, lipid for parenteral nutrition
Antibiotics (especially β-lactams, vancomycin, metronidazole)
High rate of flow of IV fluid (>90 mL/hour)
Disinfection of insertion site before catheter insertion
	None vs. chlorhexidine/alcohol
Frequent IV Dressing Changes
	Daily vs. every 48 hours
Catheter-related infection
Host factors
“Poor-quality” peripheral veins
Insertion site
	Upper arm, wrist vs. hand
Age
	Children: older vs. younger
	Adults: younger vs. older
Sex
	Female vs. male
Race
	White vs. African American
Underlying medical disease
	Individual biologic vulnerability
Factors shown not to increase risk in well-controlled, prospective, randomized trials include catheters made of polyethylene vs. siliconized elastomer or of Teflon vs. siliconized elastomer; type of antiseptic solutions used for cutaneous disinfection; use of topical antimicrobial ointment or spray on catheter insertion sites; type of dressing (e.g., gauze vs. transparent polyurethane dressing); dressing change every 48 hour vs. not at all; administration of infusate by gravity flow vs. pump; administration of IV antibiotics by slow infusion vs. “IV push” over 2 minutes; maintenance of heparin locks with saline vs. heparinized saline; and frequency of routine change of IV delivery system.
^aDenotes significantly greater risk of phlebitis; factors found to be significant predictors of risk in a prospective study of 1,054 peripheral IV catheters at the University of Wisconsin Hospital and Clinics.
IV, intravenous.
From Maki DG, Ringer M. Risk factors for infusion-related phlebitis with small peripheral venous catheters. A randomized controlled study. Ann Intern Med. 1991;114:845-854, with permission.

The microorganisms most frequently implicated in suppurative phlebitis are predominantly Staphylococcus aureus and Candida sp. (28,29,30,31). Although coagulase-negative staphylococci commonly cause IVDR-BSI, they rarely cause suppurative thrombophlebitis, possibly because of their lesser tendency to bind to host-derived protein components of thrombus compared with other pathogens such as S. aureus (33,34).

Suppurative phlebitis of peripheral IV catheters is now rare, and the syndrome of IV suppuration is predominantly a complication of CVCs, characteristically catheters that have been left in place for many days in heavily colonized ICU patients.

BLOODSTREAM INFECTION FROM CONTAMINATED INFUSATE

It is also important to recognize that the infusate—parenteral fluid, blood products, or IV medications—administered through an intravascular device also can become contaminated and produce infusion-related BSI, which is more likely than cannula-related infection to culminate in frank septic shock. Contaminated fluid is a rare cause of endemic infection with short-term peripheral IV devices, but the infusate is more commonly associated with infections of catheters used for hemodynamic monitoring, CVCs, and, possibly, surgically implanted cuffed Hickman or Broviac catheters (35,36,37,38). Most healthcare-associated epidemics of infusion-related BSI, however, have been traced to contamination of infusate by gram-negative bacilli, introduced during its manufacture (intrinsic contamination) (25) or during its preparation or administration in the healthcare system (extrinsic contamination) (1,2,39,40).

DIAGNOSIS OF INFUSION-RELATED BLOODSTREAM INFECTION

CLINICAL FEATURES

Although meticulous aseptic technique during cannula insertion and good follow-up care greatly reduce the risk of IVDR-BSI, sporadic episodes and even epidemics can still be expected occasionally to occur because of human error, intrinsically contaminated products, or the undue susceptibility to infection of many patients. If affected patients are to survive, the causal relationship between an infusion and the BSI must be recognized as early as possible.

TABLE 38.3 Clinical, Epidemiologic, and Microbiologic Features of Intravascular Device-Related Bloodstream Infection

Nonspecific	Suggestive of Device-Related Etiology
Fever	Patient unlikely candidate for bloodstream infection (e.g., young, no underlying diseases)
Chills, shaking, rigors^a	Source of bloodstream infection inapparent
Hypotension, shock^a	No identifiable local infection
Hyperventilation	Intravascular device in place, especially central venous catheter
Respiratory failure	Inflammation or purulence at insertion site
Gastrointestinal^a	Abrupt onset, associated with shock^a
Abdominal pain, vomiting	Bloodstream infection refractory to antimicrobial therapy, or dramatic improvement with removal of cannula and infusion^a
Diarrhea	Bloodstream infection caused by staphylococci (especially coagulase-negative
Neurologic^a	staphylococci), Corynebacterium (especially JK-1) or Bacillus spp., Candida,
Confusion	Trichophyton, Fusarium, or Malassezia spp.
Seizures
^aCommonly seen in overwhelming gram-negative bloodstream infections originating from contaminated infusate, peripheral suppurative phlebitis, or septic thrombosis of a central vein.

The general clinical features of infusion-related bacteremia or fungemia are nonspecific and indiscernible from BSIs arising from any local site of infection, such as urinary tract infection (UTI) or surgical site infection (SSI) (Table 38.3). There also appears to be a poor correlation between clinical judgment and microbiologic confirmation of IVDR-BSI (41). Infusion-related BSI occurring in ICU patients can be particularly insidious: bacteremia or fungemia is usually identified by positive blood cultures, but is attributed to healthcare-associated pneumonia, UTI, or SSI, or is simply accepted as “cryptogenic” and treated empirically.

Certain clinical, epidemiologic, and microbiologic findings can be extremely helpful to the clinician evaluating a hospitalized patient with a picture of healthcare-associated BSI or cryptogenic bacteremia or candidemia, and point toward an IVD as the source (Table 38.3):

The patient is an unlikely candidate for BSI, being healthy and without underlying predisposing diseases (25,42).
No local infection to account for a picture of BSI (25,42).
An IVD in place, especially a CVC, at the outset of BSI (42).
Local inflammation (21,26,27,43), especially purulence at the insertion site (27,43), which while present in only a minority of instances, is strongly suggestive of a catheter-related infection.
Abrupt onset, associated with fulminant shock—suggestive of massively contaminated infusion (44).
Healthcare-associated BSI caused by staphylococci (42), especially coagulase-negative staphylococci, Corynebacterium (especially JK-1), or Bacillus spp., or Candida (42), Fusarium, Trichophyton, or Malassezia spp., suggests IVDR-BSI. In contrast, bacteremia caused by streptococci, aerobic gram-negative bacilli—especially Pseudomonas aeruginosa—or anaerobes is very unlikely to have originated from an infected IVD (42).
BSI refractory to antimicrobial therapy or dramatic improvement with removal of the cannula or discontinuation of the infusion (25,42).

During a large, nationwide outbreak in 1970 to 1971 due to intrinsic contamination of one U.S. manufacturer’s products, patients treated with antibiotics to which the epidemic organisms were susceptible remained clinically septic, continued to have positive blood cultures after 24 hours or more of appropriate therapy, and did not improve clinically until their infusions were serendipitously or intentionally removed (25).

Focal retinal lesions—cotton-wool spot patches—may be seen in patients with disseminated Candida spp. infection deriving from CVCs, even in those without positive blood cultures (45). Careful ophthalmologic examination should be routinely performed in the evaluation of patients with CVCs with suspected IVDR-BSI, especially patients receiving total parenteral nutrition (TPN). BSI from arterial catheters may be heralded by embolic lesions that manifest as tender, erythematous papules, 5 to 10 mm in diameter, appearing in the distal distribution of the involved artery, usually in the palm or sole—Osler nodes (46,47). Arterial bleeding from the insertion site is often the harbinger of BSI caused by an infected arterial catheter and may denote an infective pseudoaneurysm (46,48,49). Endocarditis, particularly right-sided, is a rare but well-documented complication of flow-directed pulmonary artery catheters (50,51,52).

BLOOD CULTURES

Blood cultures are essential to the diagnosis of IVDR-BSI (see Chapter 9), and in any patient suspected of infusion-related infection, two or three separate 10-mL blood cultures should be drawn (53,54,55), ideally from peripheral veins, by separate venipunctures. If the patient is receiving antimicrobial therapy, blood cultures obtained immediately before a dose is due to be administered—when blood antibiotic levels are likely to be low—may provide a higher yield. The use of resin-containing media to adsorb and remove any antibiotic present in the blood specimen (56), adsorb serum factors detrimental to the growth of Enterobacteriaceae (57), and lyse the cell wall of neutrophils, thereby releasing intracellular pathogens (58), may also increase the yield (59).

The use of a biphasic system, such as the Isolator^® (E.I. DuPont, Nemours and Co., Wilmington, Delaware, USA), or systems with selective high-blood-volume fungal media (BACTEC; Becton Dickinson Diagnostic Instrument Systems, Sparks, Maryland, USA) appear to significantly enhance the laboratory detection of fungemia (60,61). However, quantitative blood cultures are labor-intensive and cost almost twice as much as standard blood cultures. The wide availability of radiometric blood culture systems (BACTEC system; Becton Dickinson, Sparks, Maryland, USA), in which blood cultures are continuously monitored for microbial growth (approximately every 20 minutes), has led to a clever application of this system for the detection of IVDR-BSI (62). The differential time to positivity (DTP) of blood cultures drawn through the IVD and concomitantly from a peripheral vein has been evaluated as a surrogate for paired quantitative blood cultures. The detection of positivity in a blood culture drawn from the IVD >2 hours before positivity of the culture drawn from a peripheral site has been shown to be highly predictive of IVDR-BSI in several studies of both short- and long-term catheters (62,63). In a meta-analysis of 49 studies evaluating eight different methods for diagnosis of IVDR-BSI, DTP had a sensitivity of 0.90 and specificity of 0.83 (27).

The volume of blood cultured is critical to maximize the yield of blood cultures for diagnosis of bacteremia or candidemia: in adults, obtaining at least 20 mL, ideally 30 mL, per drawing—each specimen containing 10 or 15 mL, inoculated into aerobic and anaerobic media—significantly improves the yield, compared with obtaining only 10 mL at each drawing and culturing a smaller total volume (64,65). It is rarely necessary to obtain >2 15-mL cultures or three 10-mL cultures in a 24-hour period. If at least 30 mL of blood is cultured, 99% of detectable bacteremias should be identified (64).

It is common practice in many ICUs to draw blood cultures through central venous or arterial catheters or, in neonates, through umbilical catheters. Comparative studies of standard blood cultures drawn through central venous or arterial catheters in adults usually have shown good concordance with cultures drawn by percutaneous peripheral venipuncture (66,67,68), but rates of false-positive (contaminated) cultures can be considerably higher with catheter-drawn specimens (69,70,71). The practice of drawing nonqualitative blood cultures through indwelling vascular catheters probably ought not to be encouraged because of the risk of introducing contamination during the manipulation (72).

If the laboratory has an automated quantitative system available for culturing blood, such as the Isolator^® system, catheter-drawn blood cultures can permit the diagnosis of IVDR-BSI to be made with reasonable sensitivity and specificity (both in the range of 90%), without removing the catheter (73,74,75,76,77,78,79). With infected catheters, a quantitative blood culture drawn through the catheter usually shows a marked step-up—often >10-fold—in the concentration of organisms compared with quantitative blood cultures drawn at the same time percutaneously through a peripheral vein.

Quantitative catheter-drawn blood cultures probably have their greatest utility in diagnosis of device-related infection with surgically implanted cuffed Hickman or Broviac catheters and subcutaneous central venous ports (73,74,75,76).

Finding microbes on Gram stain or acridine orange stain of blood drawn through CVCs has been shown to be highly sensitive and specific for diagnosing IVDR-BSI (80,81). If confirmed by others using the same and other IVDs, these may be the methods of choice for the rapid diagnosis of serious intravascular catheter-related infections. Intracellular bacteria have been found on Wright-stained peripheral smears in asymptomatic patients with occult CVC-BSI (82).

MICROBIOLOGY OF INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTION

The microbiologic profile of BSI (Table 38.3) can strongly suggest an infusion-related source. Cryptogenic staphylococcal BSI, particularly with coagulase-negative staphylococci, BSI caused by Bacillus or Corynebacterium (especially JK-1) spp. or Enterococcus, or fungemia caused by Candida, Fusarium, Trichophyton, or Malassezia spp., especially in a patient with a CVC, is most likely to reflect a catheter-related infection (1,2,42).

BSIs caused by Enterobacter cloacae or, especially, Pantoea (formerly Enterobacter) agglomerans, Burkholderia cepacia, Stenotrophomonas maltophilia, or Citrobacter spp., in the setting of infusion therapy, may signal an epidemic and should prompt studies to rule out contaminated infusate (83). A BSI cluster should mandate a full-scale investigation, which may include culturing of large numbers of in-use infusions and informing the local, state, and Federal public health authorities. Such actions averted a large, nationwide epidemic in 1973, when, prompted by five unexplained BSIs in three hospitals, intrinsic contamination of one U.S. company’s products was identified and a recall put into effect so rapidly that the outbreak was limited to the five initially recognized patients (84). It must be emphasized, however, that for BSI surveillance to be maximally effective, all blood culture isolates must always be fully identified—that is, identified to the genus and species level. Failure to do so during the 1970 to 1971 nationwide epidemic traced to the contaminated products of one U.S. manufacturer resulted in preeminent hospitals experiencing large numbers of infections that were recognized as infusion-related only in retrospect (25).

Cryptogenic healthcare-associated BSI caused by psychrophilic (cold-growing) organisms, such as non-aeruginosa pseudomonads, Ochrobactrum anthropi (formerly Achromobacter), Flavobacterium, Enterobacter, or Serratia spp. (85,86), or by Salmonella (87) or Yersinia spp. (88), with a picture of overwhelming BSI, may indicate a contaminated blood product.

CULTURES OF INTRAVASCULAR DEVICES

Some laboratories still culture vascular catheters qualitatively, amputating the tip aseptically and immersing it in liquid media. Unfortunately, a positive culture by this technique is diagnostically nonspecific because a single organism picked up from the skin as the catheter is removed can produce a positive—false-positive—culture (89). Many IVDR-BSIs derive from local infection of the transcutaneous cannula tract (see discussion later). The culture of the external surface of the withdrawn cannula should reflect the microbiologic status of the wound, and quantitative culture should more accurately distinguish infection from contamination. A standardized, semiquantitative method for culturing vascular cannulas in solid media was developed in 1977 (21). Colony counts on semiquantitative culture are bimodally distributed, as they are in quantitative urine cultures. The method provides excellent discrimination between colonization and insignificant contamination acquired during catheter removal. Fifteen or more colony-forming units (cfu) growing on a semiquantitative plate is regarded as a positive culture, and denotes significant growth or colonization (21). On the basis of experience with >10,000 IVDs, positive cultures found using this technique have shown a 15% to 40% association with concordant BSI. Cannulas positive on semiquantitative culture also are strongly associated with local inflammation (21).

A good correlation between high colony counts and IVDR-BSI has been demonstrated with cultures of catheter segments semiquantitatively on solid media (90,91,92) or quantitatively in liquid media—removing organisms from the catheter by vortexing or sonication (90,93,94). The latter techniques appear to have the greatest sensitivity and specificity for the diagnosis of vascular catheter-related infection (95,96). However, a negative catheter culture may not rule out a catheter-related BSI (CR-BSI) (37

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