Emerging Issues in Antibiotic Resistance in Blood-borne Infections

GEORGE H. KARAM and JOHN E. HEFFNER

Louisiana State University Health Sciences Center School of Medicine in New Orleans, Louisiana; and Medical University of South Carolina, Charleston, South Carolina

	INTRODUCTION

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Major shifts in drug susceptibility patterns of microbial pathogens in the intensive care unit (ICU) have forced intensivists to alter their antibiotic management of critically ill patients. Physicians must now select antibiotics with the specific needs of an individual patient in mind but also in a manner that does not breed further drug resistance. This update reviews emerging concepts in the development and management of antibiotic resistance of selected pathogens affecting critically ill patients. We have selected for review mechanisms of drug resistance that have received recognition as new threats to infection control, emerging innovations in managing antibiotic resistance, and pathogens that present the greatest potential for altering our critical care practices. Other sources exist for a discussion of the development and control of antibiotic resistance in general and the impact of antibiotic resistance on traditional nosocomial pathogens (1).

	GENERAL MECHANISMS OF ANTIBIOTIC RESISTANCE

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Multiple mechanisms exist for ICU pathogens to acquire antibiotic resistance. These mechanisms include enzymatic inhibition of drugs, alteration of proteins targeted by antibiotics, changes in metabolic pathways, antibiotic efflux, alterations in porin channels, and changes of membrane permeability (7).

Extensive data indicate that ICUs are the epicenter for spawning multidrug resistance within hospitals (9). Many patients are transferred to the ICU from other healthcare facilities, where they have acquired resistant pathogens. Patients within the ICU undergo invasive procedures, treatment with antibiotic combinations, and exposure to other patients with resistant pathogens. Increasing numbers of immunocompromised patients are cared for in the ICU. Some ICUs utilize oral bowel decontamination prophylactic measures that can promote resistant pathogens (10). Lapses in aseptic techniques frequently occur in the ICU (11). And, most patients transfer to other areas of the hospital after stabilization, rather than being discharged directly home, which allows spread of ICU-acquired infections.

	GENERAL INFECTION CONTROL INTERVENTIONS

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No single infection control approach can stem the development of resistant pathogens in the ICU (8). The Society of Healthcare Epidemiology of American and the Infectious Diseases Society of America have developed guidelines to promote infection control in hospitals (12) (Table 1).

The strength of data supporting effectiveness of these interventions varies. Patient isolation, barrier precautions, and use of dedicated instruments (e.g., stethoscopes) are supported by evidence indicating that cross-contamination of patients is an important mechanism for spread of resistant pathogens. Patients are at increased risk of acquiring vancomycin-resistant enterococcus (VRE) if they are in proximity to a patient with VRE or are cared for by a nurse assigned other patients with VRE (13). Environmental fomites, such as door knobs, bed rails, and stethoscopes, harbor viable VRE for as long as 1 wk (14). These observations have promoted the use of "cohort nursing" wherein a single nurse is assigned patients who harbor pathogens with similar resistance patterns.

The strongest evidence exists for the utility of frequent hand washing between patients and the use of appropriate aseptic techniques (11). The utility of patient isolation is less well established because this intervention has usually been studied in combination with antibiotic class restrictions. One study, however, demonstrated effectiveness of isolation measures alone in controlling a prolonged outbreak of resistant Enterobacteriaceae (9).

	SELECTIVE PRESSURE AND HOMOGENEOUS ANTIBIOTIC PRESCRIBING

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Data suggest that avoidance of overuse of an antibiotic class suppresses emergence of drug resistant pathogens by decreasing selective pressure. Selective pressure pertains to environmental conditions that promote proliferation of resistant pathogens (15). Although selective pressure may occur in nonmedical settings, such as with the use of antibiotics for farm animals raised for meat and produce, antibiotic prescribing for patients is the primary factor in generating resistant pathogens (16).

It appears that prescribing patterns have different capacities to produce selective pressure depending on whether antibiotics are used in a homogeneous or heterogeneous manner. Homogeneous antibiotic prescribing denotes use of a single or limited number of preferred antibiotics as "workhorse" drugs for empiric therapy. Homogeneous drug prescribing has been fostered by restrictive formularies designed to decrease drug costs and prevent emergence of resistance against antibiotics "held in reserve." Restrictive formularies, however, apply selective pressure and promote resistance against the specific antibioticand often the entire antibiotic classused (17). Homogeneous prescribing can also promote linked cross-resistance, wherein heavy use of one class of antibiotics can induce resistance in another class of drugs.

	HETEROGENEOUS ANTIBIOTIC USE AND "CROP ROTATION"

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Infection control guidelines include the rotation of antibiotics, also termed "heterogeneous antibiotic use," for controlling resistant pathogens. The heterogeneous use of antibiotics rotates antibiotics to effectively treat an individual patient while decreasing selective pressure. The theory of homogeneous antibiotic prescribing is directed toward preventing drug resistance (17). Heterogeneous prescribing recognizes that the emergence of drug-resistant strains in an ICU is inevitable and provides an approach for managing resistance and limiting its spread.

Several approaches promote heterogeneous use of antibiotics. Computer-assisted antibiotic prescribing presents clinicians at order entry with drug recommendations based on the clinical characteristics of the patient, antibiotic susceptibilities of the suspected pathogen, and recent antibiotic prescribing patterns. Computer-based systems have been shown to (1) prevent use of agents to which patients are allergic, (2) promote appropriate drug dosages, (3) decrease bacterial antibiotic-susceptibility mismatches, (4) decrease duration of excessive antibiotic use, (5) decrease antibiotic-related adverse events, (6) decrease drug costs, (7) decrease total hospital costs, (8) decrease length of hospital stay, and (9) limit the emergence of resistant pathogens (18).

Scheduled rotation of antibiotics in an ICU represents another effort to promote heterogenous prescribing (19). Termed "crop rotation," antibiotic classes used for empiric therapy for suspected infections are rotated over a specific period of time. For instance, a fourth-generation cephalosporin might represent the preferred antibiotic for empiric therapy during a 3-mo period, followed in the next 3 mo by a fluoroquinolone, then by a carbapenem, and finally by a -lactam/-lactamase inhibitor combination, after which the rotation begins again.

The efficacy of a "crop rotation" approach for limiting antibiotic resistance requires further confirmation considering that selective pressure from one class of antibiotics can promote microbial resistance to other classes (20, 21). Additional research is needed to determine the ideal duration of antibiotic administration before drugs are rotated and the optimal order of rotation between different antibiotic classes.

Physician education in the appropriate and judicious use of antibiotics remains the most important element in limiting emergence of resistant pathogens. Studies indicate that the selection of an appropriate initial antibiotic regimen for empiric therapy decreases mortality (22) and limits the emergence of drug resistance (23).

	RESOURCES FOR SELECTING EMPIRIC ANTIBIOTICS FOR BLOOD-BORNE INFECTIONS

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Several sources of information exist on the frequency of different pathogens as causes of blood-borne infections to assist physicians in selecting appropriate empiric therapy. Three sources that provide representative information include data from (1) the Centers for Disease Control and Prevention National Nosocomial Infections Surveillance (NNIS) system (24); (2) the NNIS system on adult medical intensive care units (25); and (3) a consortium of 49 hospitals across the United States (26) (Table 2).

Sources of information on patterns of drug resistance also assist physicians in initiating appropriate empiric therapy. Although drug resistance varies by location, aggregate national data identify emerging pathogens with clinically important resistance patterns. The CDC Hospital Infections Program and Emory University have developed Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE), which monitors antimicrobial resistance at a subset of hospitals participating in the NNIS system. Phase 2 of Project ICARE identified 12 sentinel resistant organisms, listed in Table 3 (27).

Project ICARE detected an important shift in antibiotic resistance patterns; some gram-negative pathogens were more likely to demonstrate drug resistance when isolated from non-ICU as compared with ICU settings (27). The reversal of the traditional pattern of more resistance in the ICU appears to have occurred because of the heavy outpatient use of broad-spectrum oral antibiotics. This observation underscores the importance of determining if critically ill patients have undergone recent treatment with oral antibiotics, which increases the probability of resistant pathogens.

	DRUG RESISTANCE ISSUES WITH SPECIFIC PATHOGENS

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Blood-stream infections represent the most life-threatening infectious condition affecting critically ill patients. The remainder of this review discusses specific blood-borne organisms reported in the United States in recent years that present the greatest potential for affecting critically ill patients. More traditional ICU nococomial pathogens and pathogens that have been more extensively discussed in the literature during the last several years are presented elsewhere (16, 20, 28).

Infections Caused by Gram-Negative Bacilli

Escherichia coli and Klebsiella pneumoniae are the most common gram-negative pathogens that infect hospitalized patients (24, 25). Their management has become complicated by their generation of a variety of -lactamases.

-Lactamases are either Type 1 or non-Type 1 enzymes. Type 1 -lactamases are produced through chromosomally mediated mechanisms. Non-Type 1 -lactamase resistance takes several forms, of which the transfer of extended-spectrum -lactamases (ESBLs) between bacteria is becoming increasingly clinically relevant.

ESBLs appear to result from heavy use of broad-spectrum cephalosporins (29). Extensive outpatient use of oral trimethoprim/sulfamethoxazole and ciprofloxacin may facilitate spread of ESBL-producing bacteria (30).

ESBLs are mutant enzymes created by one or more amino acid substitutions in the common TEM-1 and SHV-1 -lactamases (31). Genes encoding ESBLs are typically carried on large, self-transferable plasmids that carry resistance factors for many other classes of antibiotics (32). The simplicity of this mutation in a common enzyme system and the broad pattern of resistance that results underscore the importance of ESBLs.

Because of variability of laboratory testing policies for ESBLs (33), drug susceptibility patterns of ESBL-producing organisms may be reported inaccurately. Most laboratories report strains of K. pneumoniae and E. coli with a minimal inhibitory concentration (MIC)  8 µg/ml as susceptible to ceftazidime (34). Bacterial strains with ceftazidime MIC values of 2-4 µg/ml, however, may produce ESBLs. The existence of ESBLs, therefore, should be suspected when Enterobacteriaceae have ceftazidime MICs  2 µg/ml (34). Unfortunately, most laboratories do not report specific MIC values and simply indicate that bacteria with MIC values  8 µg/ml are "susceptible." Because ceftazidime is the most susceptible of the extended-spectrum cephalosporins to undergo hydrolysis by ESBLs (31), ESBLs should be suspected when K. pneumoniae and E. coli exhibit ceftazidime resistance.

Clinical factors that identify patients at risk for ESBL bacteria include previous therapy with cephalosporins (30, 35- 37), aztreonam (37), ciprofloxacin and/or trimethoprim/sulfamethoxazole (30), poor functional status (30), high APACHE II scores (37), presence of a decubitus ulcer (30), ICU stay > 5 d (38), and previous instrumentation with gastrostomy tubes, urinary catheters, arterial catheters, and other invasive procedures (37, 38).

Bacteria that produce ESBLs should be considered resistant to all penicillins, cephalosporins other than cephamycins (e.g., cefoxitin and cefotetan), and aztreonam (33, 39). Moreover, third-generation cephalosporins, such as cefotaxime and ceftriaxone, with reported MICs in the susceptible range against ESBL-producing bacteria, may fail in vivo because of an "inoculum" effect, which raises the MIC as bacterial load increases (31, 40, 41). Consequently, ESBL-producing strains should be considered resistant to all third-generation cephalosporins regardless of susceptibility results (34). Although fourth-generation cephalosporins are usually stable in the presence of Type I -lactamases, cefepime is not predictably stable in the presence of ESBLs (42, 43).

Because ESBL-containing plasmids often carry resistance genes for other antibiotics, gentamicin, tobramycin, and fluoroquinolones may be ineffective (44). ESBLs may also confer resistance to -lactamase inhibitor drug combinations because sufficient -lactamase is produced to overwhelm available inhibitor concentrations. Although -lactam/-lactamase inhibitors combinations have been suggested as an option for ESBL producers, these drugs must be given in high doses (39). Presently, carbapenems, such as imipenem and meropenem, are the most stable antibiotic class in the presence of ESBLs.

In initiating empiric therapy, clinicians must balance the importance of treating serious ESBL bacterial infections with carbapenem-containing antibiotics and the risk of generating resistance to carbapenem drugs by their overuse (45). Fortunately, reports of carbapenem resistance in Pseudomonas aeruginosa and K. pneumoniae that developed during therapy of ESBL outbreaks resulted from decreased permeability to drug rather than plasmid-mediated mechanisms and did not confer resistance to other antibiotic classes (46, 47). Resistance to carbapenems by altered permeability is usually amenable to infection control procedures (46).

A staged approach to carbapenem use is indicated when managing patients suspected of harboring ESBL-producing organisms. No antibiotics are indicated for colonization with ESBL-producing organisms without infection. Patients with mild to moderate infections with risk factors for ESBL-producing bacteria may be empirically treated with noncarbapenem drugs, such as piperacillin-tazobactam, pending culture and drug susceptibility reports. Patients with risk factors for ESBL-producing bacteria and clinical signs of severe infection should be treated with regimens containing a carbapenem. Carbapenems are reserved for patients with severe infections with risk factors for ESBLs because the large number of critically ill patients with risk factors would otherwise lead to overuse of carbapenems.

Enterococcal Infections

Only 20 years ago, controversy existed about whether enterococci were common causes of nosocomial infections or commensals in the ICU (48). The 1984 NNIS report of blood-borne pathogens indicated that enterococci accounted for only 7% of isolates (49). The NNIS report of 1992-1997 data, however, found that enterococci comprised 16% of blood-borne isolates in adult patients cared for in medical ICUs (25).

Enterococci develop resistance through acquired mechanisms, which include gene transcription and acquisition of DNA via plasmids and transposons (genetic elements that can move from one location on DNA to another within and between bacteria), and through intrinsic mechanisms (15, 39, 50). Enterococcal plasmids can transfer resistance to other gram-positive bacteria, which presents a mechanism for spreading vancomycin resistance to staphylococci and streptococci.

Intrinsic resistance is a natural property of enterococci and does not require a change in the bacteria or previous exposure to antibiotics (51). For instance, enterococci are intrinsically resistant to cephalosporins as a drug class. Intrinsic resistance of enterococci to cephalosporins may explain their emergence as prominent pathogens in the ICU via selective pressure from the widespread use of cephalosporins during the 1980s and 1990s (52). Some species of entercocci, such as Enterococcus gallinarium and Enterococcus casiflavis, have intrinsic resistance to vancomycin.

Enterococci, usually Enterococcus faecium, with acquired resistance to glycopeptide antibiotics (e.g., vancomycin and teicoplanin) and resistance to all -lactam antibiotics, appeared in the mid-1980s after a period of increasing prophylactic and therapeutic use of vancomycin (39). It is suspected that widespread use of antibiotics with poor activity against VRE promoted the emergence of these pathogens. Ticarcillin, ceftazidime, and ceftriaxone provide no suppressive activity against VRE in the intestinal tract (55). Use of these drugs allows intestinal VRE to flourish in contrast to antibiotics, such as ampicillin and piperacillin, which reach high concentrations in bile and suppress intestinal VRE (56). Extensive use of antibiotics with activity against anaerobic bacteria has also been reported to promote colonization and infection with VRE (57, 58), possibly by altering the intestinal flora.

Vancomycin use also promotes expression of vancomycin resistance in enterococci (50). Vancomycin induces transcription of genes that translate into enzymes that produce cell wall precursors. Vancomycin binds with low affinity to these precursors because of alterations in their terminal amino acid sequences. Other induced genes suppress the synthesis of cell wall precursors that have a high affinity for vancomycin (59). Antibiotic use alone, however, will not select for VRE if resistant enterococci do not already exist in the patient or in the patient's environment (60).

Effective therapeutic options for vancomycin-resistant enterococcal infections are limited. These pathogens are resistant to synergism with gentamicin and streptomycin and commonly demonstrate resistance to multiple antibiotics, including ampicillin, rifampin, and fluoroquinolones. In some instances of deep-seated VRE infection, high-dose ampicillin or ampicillin-sulbactam may retain clinical efficacy if the minimum inhibitory concentration for ampicillin is  64 µg/ml (39). Gentamicin or streptomycin should be added unless the enterococci are highly resistant to these antibiotics. Patients with lower urinary tract infections with VRE may be treated with nitrofurantoin, ampicillin, amoxacillin, or fosfomycin, although limited data on efficacy are available for these drugs (60).

The streptogramins represent a new class of antibiotics, with quinupristin/dalfopristin (Synercid) being the first drug in this class to obtain Food and Drug Administration approval. The spectrum of activity is limited to only certain aerobic gram-positive microorganisms, which include vancomycin- resistant and multidrug-resistant E. faecium. Quinupristin/dalfopristin is not active against E. faecalis, which represents the most common enterococcal isolate in clinical infections. Quinupristin/dalfopristin treatment of patients who are colonized with VRE can promote resistance to this antibiotic (61); patients with VRE colonization should not receive quinupristin/ dalfopristin therapy. Linezolid is the first oxazolidinone antibiotic to be approved for use by the FDA. It is active in vitro against VRE, although it is not bactericidal at achievable plasma concentrations (60). Its role in the therapy of VRE has not been clearly defined.

Unfortunately, no definitive guidelines exist for discriminating between infection and colonization when enterococci are isolated from critically ill patients. The pathogens, however, have a typical pattern of detection. They are usually isolated from critically ill patients who have multiple health problems. Although enterococcal bacteremia may occur at the time of death, the attributable mortality from these pathogens is unclear. Entercoccal species are commonly isolated from wounds but, in most institutions, are not common pathogens in deep-seated infections. When deep-seated infections do occur, they are usually related to infections of the biliary and urinary tract although enterococcal endocarditis does occur. It is unclear that enterococci are true pathogens when they are isolated from sputum or a soft-tissue site. Enterococcal bacteremia often occurs as a consequence of a central venous catheter infection.

Reducing the use of vancomycin and infection control measures to prevent person-to-person spread are the most important measures for decreasing infections with VRE in the ICU.

Candidal Infections

Approximately one-half of all inpatient Candida infections occur in surgical ICUs, reflecting the importance of the alimentary tract as a source of Candida infection. Candida outbreaks are serious concerns because of the ability of this pathogen to spread from patient to patient and caregiver to patient (62).

The attributable mortality of candidemia ranges from 40 to 60% (63), which is higher than the attributable mortality of bacterial blood-borne infections (26). Different Candida species have differing effects on mortality. Patients with hematologic and solid tumor malignancies have a lower mortality with fungemia due to Candida parapsilosis as compared with Candida albicans (64). Although some experts contend that fungemia due to Candida glabrata, Candida tropicalis, and Candida krusei is associated with the worst outcomes, this observation is not yet well established.

Deep-seated Candida infections often defy detection. Only 50% of neutropenic patients found at autopsy to have metastatic Candida infections had positive antemortem blood cultures (65). More than 80% of neutropenic patients with fungemia due to C. albicans and C. tropicalis are found to have disseminated fungal infections at autopsy (66, 67). More than 30% of surgical patients who received incomplete fungal therapy for transient fungemia as a late complication of intraperitoneal infection have autopsy evidence of visceral fungal microabscesses (68).

Metastatic Candida infections should be suspected with the sudden onset of high-grade candiduria that occurs in the absence of vaginitis in a woman and bladder catheterization in either sex (69). Risk factors for candidemia include (1) previous antibiotic use, (2) indwelling catheters, (3) hyperalimentation, (4) cancer therapy, (5) immunosuppressive therapy after organ transplantation, (6) ICU admission, (7) candiduria, and (8) colonization with Candida species (62). The risk for deep- seated Candida infection is multiplicative with the presence of two or more risk factors (70).

The noticeable increase in the frequency of infections caused by non-albicans Candida species and the appearance of candidal isolates resistant to both amphotericin B and the newer azoles represent two important alterations in the pattern of Candida infections. Susceptibility patterns for different Candida strains to fluconazole vary from an MIC₅₀ of 0.25 µg/ml for C. albicans to 32 µg/ml for C. krusei (62). Candida lusitaniae demonstrates low susceptibility or outright resistance to amphotericin B.

Heavy use of azoles has been linked to a shift toward non-albicans species of Candida in the ICU (71, 72). In a study from the European Organization for Research and Treatment of Cancer (64), 31% of blood-borne Candida isolates represented breakthrough fungemia in the presence of antifungal therapy. Non-albicans species of Candida were isolated in 65% of breakthrough fungemias. These observations suggest that antifungal agents, especially when used as prophylaxis, may select for emergence of non-albicans species and promote drug-resistant strains.

Because of risks for promoting drug-resistant strains, the evidence for benefit from antifungal prophylaxis warrants review. Fluconazole primary prophylaxis has been shown to be effective for patients undergoing bone marrow transplantation, decreasing mortality from acute systemic fungal infections from 5.6 to 0.6% (73). These results support use of fluconazole to prevent fungal infections in bone marrow transplantation patients, which is the only indication for fluconazole primary prophylaxis that has FDA approval. Liver transplant patients have also been shown to benefit although this patient population does not have an FDA indication for antifungal prophylaxis.

Limited data are available regarding the utility of fluconazole as primary prophylaxis for critically ill patients. One study detected benefit from fluconazole prophylaxis for patients with abdominal surgery and recurrent anastomic leaks (74). These findings cannot yet be extrapolated to other populations of surgical patients.

An international consensus conference has developed guidelines for initiating antifungal prophylaxis for critically ill patients (62). Prophylaxis should be considered for patients with all of the following clinical features: (1) antibacterial therapy for > 14 d, (2) indwelling venous catheters, (3) hyperalimentation, (4) Candida isolated  2 sites, and (5) complicated intraabdominal surgery (62).

Marr and coworkers examined fluconazole prophylaxis in bone marrow transplantation (75). They found that fungemia during fluconazole prophylaxis was due to fluconazole-resistant candidal species. This observation suggests that prolonged prophylaxis with fluconazole is an important determinant in selecting initial antifungal therapy for patients with suspected candidal infections. Patients with unexplained fever and risk factors for candidemia who have not received fungal prophylaxis with an azole drug may be considered for therapy with fluconazole. Amphotericin B is the preferred initial therapy if patients have received fluconazole prophylaxis or if a high prevalence of non-albicans Candida species exists in the treating institution.

Care is required to determine if isolation of Candida species from two or more sites represents colonization or infection. For instance, Candida isolated from the urine of a patient who has risk factors for candidemia and unexplained, persistent fever could reflect hematogenous seeding of the kidney. These circumstances would warrant the initiation of antifungal agents for therapy rather than prophylaxis. Conversely, positive urine cultures in a patient without clinical evidence of systemic infection and without other risk factors for candidemia warrants no antifungal therapy.

The mechanisms by which C. albicans develops resistance to fluoconazole are diverse (76). They include alterations in target site, sterol biosynthesis, efflux, and uptake. The most important mechanism clinically appears to be reduced access of the drug to the intracellular P450 14 DM target, due to a multidrug resistance efflux pump, and overproduction of the P450 14 DM target. Other possible mechanisms for azole resistance remain to be identified.

	SUMMARY

TOP INTRODUCTION GENERAL MECHANISMS OF... GENERAL INFECTION CONTROL... SELECTIVE PRESSURE AND... HETEROGENEOUS ANTIBIOTIC USE... RESOURCES FOR SELECTING EMPIRIC... DRUG RESISTANCE ISSUES WITH... SUMMARY REFERENCES

Emerging patterns of antibiotic resistance have altered outcome for critically ill patients. Physicians increasingly face challenges to provide their patients with effective regimens while using antibiotics in a manner that does not breed further drug resistance. Unfortunately, no single approach promises to eliminate drug-resistant pathogens. Consequently, critical care providers must maintain a clear understanding of the prophylactic and therapeutic use of antibiotics, stay abreast of the prevalence of various pathogens and resistance patterns in their institutions, and exercise good judgment in selecting empiric antibiotic regimens.

	Footnotes

Correspondence and requests for reprints should be addressed to John E. Heffner, MD, Pulmonary Division 812 CSB, Medical University of South Carolina, 96 Jonathan Lucas Street, P.O. Box 250623, Charleston, SC 29425.

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