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Routes of bacterial contamination of intravascular catheters
ROUTES OF BACTERIAL C O N T A M I N A T I O N OF INTRA VASCULAR CA THETERS mplications for the diagnosis a n d p r e v e n t i o n ' c a t h e t e r r e l a t e d sepsis . . . . ITGES-SERRA, T. PI-SUIVER*, A. OLIVA, M. GIRVENT, M. SEGURA
In few other diseases is pathogenesis as relevant for diagnosis and prevention as is the case of catheter related sepsis (CRS). Many of the so called "controversial issues" in the field of CRS are good examples of misunderstandings arising from partial knowledge of the mechanisms whereby microorganisms gain access to the infusion system. Questions such as the value of a particular culture method, or the "in situ" diagnosis of CRS, or the relative merits of different preventive measures, can only be soundly approached once the pathogenesis of CRS is correctly understood. The aim of the present article is to describe the routes of catheter contamination and the implications that these have for correct micro-biological diagnosis and prevention of CRS.
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Pathogenesis of catheter related sepsis
Blood seeding of bacteria coming from an intravascular catheter is the end result of a complex process involving: 1) contamination of the catheter, 2) adherence of microorganisms to the internal and/or external surfaces of the catheter, 3) bacterial growth and 4) passage to the bloodstream. Each of these steps is now the object of separate studies thanks to the experimental models recently described [1, 3] which have shed much light on the intimate mechanisms underlying CRS. A brief summary of these steps is presented and a more thorough discussion on the clinical implications of the routes of catheter contamination will be discussed separately. Catheter contamination
Bacteria gain access to an intravascular catheter through four main routes: from the skin insertion site Hospital Universitari del Mar, Barcelona, Spain. * Department of Surgery and Infection Control. Correspondence to: Prof. A. Sitges-Serra, M.D., Department of Surgery, Hospital Universitari del Mar, Passeig Madtim, 25-29, 08003 Barcelona (Spain).
(puncture or cutdown), from the hub connecting the catheter with the giving set, from a contaminated infusate and from hematogenous seeding during bacteremias arising from a distant focus. Briefly, catheters get contaminated through the endoluminal or the extraluminal route. Adherence of microorganisms to catheter surfaces
After bacteria gain access to the intravascular device, it is thought that they adhere and replicate on catheter surfaces before they pass into the bloodstream in significant numbers [2]. In "in vivo" experimental studies [3], purposeful endoluminal contamination of catheters with S. warnerii was not always followed by bacterial adherence to the catheter and CRS, whereas catheters innoculated with Pseudomonas aeruginosa gave always rise to positive blood cultures and sepsis symptoms. In a report from a neonatal intensive care unit, recovery of certain species (Propionibacterium acnes, coagulase negative staphylococci) from surveillance hub cultures did not always result in CRS [4]. Thus, several factors play a role in determining bacterial adherence such as the species and strains of bacteria involved, slime production, catheter material and the type of infusate [2]. Growth of bacteria on the catheter
Bacterial adherence is followed by bacterial replication, extensive contamination of the catheter surfaces and progressively increasing seeding of microorganisms [2]. In hub related CRS the whole internal and much of the external catheter surfaces appear to be contaminated as shown by polysegmental endo and extraluminal catheter cultures [5]. According to most bacteriological studies on CRS, a critical number of bacteria contaminating the tip seems to be a prerequisite for a clinically relevant passage of bacteria to the bloodstream. R#an. Urg., 1994, 3 (3 bis), 359-364
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Bacteremia
microorganisms involved [3]. The magnitude of the innoculum and the route of infection may also be relevant but these have not been investigated in depth. Clinical experience suggests that extraluminal contamination occuring at the time of catheter insertion may lead to CRS within three to ten days.
This is the final step of CRS and gives rise to the first symptoms of the disease. Up to the present, a positive blood culture is considered to be a requisite to ascertain the diagnosis of CRS and it is generally thought that central venous catheters cannot be the source of fever in the absence of bacteremia. Bacteremia supervenes once a critical level of bacteria is surpassed, and, consequently, no matter what is the route of catheter contamination, bacteremia is always associated with a significant bacterial growth at the catheter tip. Authors using quantitative catheter cultures have defined a critical level for bacteria recovered (usually 1,000 c.f.u./mL of culture broth) to separate the concepts of "catheter infection" -with bacteremia- as opposed to "catheter colonization", not associated with clinical symptoms. These are useful concepts but, unfortunately, lack of knowledge about the relevance of endoluminal bacterial growth has created some misunderstanding about the relative value of the different culture methods and their corresponding cut-off points for bacterial growth. It is not known how much time it may take for the whole process leading to CRS to develop. In fact, little is known about the natural history of CRS, since experimental models have only been recently available. Initial results from an in vivo model developed in our laboratory suggests that time between endoluminal catheter contamination and the appearance of symptoms may depend on the virulence of the
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Routes of catheter contamination
In recent years, several papers have addressed the relative importance of the different routes of catheter contamination. The introduction of endoluminal hub cultures has helped to elucidate the epidemiology of the different mechanisms through which intravascular catheters are contaminated. Other issues facilitating the understanding of contamination mechanisms have been the recognition that catheterization time and the policy for catheter maintenance are relevant to the pathogenesis of CRS. Briefly, it can be stated that the two more relevant routes of catheter contamination are the extraluminal route, through which the microorganisms migrate from the insertion site to the catheter tip along its outer surface, and the endoluminal route, through which the microorganisms gain access to the inner catheter surface through the catheter hub. The relative importance of these two mechanisms is shown in table I, constructed from reports in which the microbiological patterns for different types of CRS [5] were appropriately recognized [4, 10]. Table I
Relative importance of different routes of contamination of intravascular catheters
Author Cercenado [8] Cicco [6] Salzman [91 Lit'iares [41 Fan [5] Weightman [7] Segura [10]
N Catheters
Cath. Time
N of CRS
Hub
Skin
Mixed
Other 1
139 109 113 22 156 42 400 4
8.6 days 18.2 days 23.9 days 20 days 15 days 114 days 23 days
53 2 6 28 20 11 11 24
12 3 21 14 1 8 9
30 3 7 2 4
8
3
5
2
2
4 4 3 3 8
1 Hematogenous seeding, infusate contamination, unknown. 2 Positive catheter tips. 3 Incomplete cultures. 4 Patients.
Extraluminal contamination (skin origin)
Crane [11] was the first to suggest that CRS was secondary to microorganisms creeping, from an infected insertion site to the bloodstream, along the catheter tract. Since then, much data have accumulated in favor of this route of contamination that continues to be the most relevant one for catheters inserted for less than a week [12]. Because of a poor skin preparation, defective surgical technique or inappropriate dressing of the fresh skin puncture, the R~an. Urg., 1994, 3 (3 bis), 359-364
wound gets contaminated at the time of catheter insertion usually with skin comensals: coagulase negative staphylococci or S. aureus. This develops into a subdermal infection spreading along the subcutaneous tract surrounding the catheter. If the catheter has been tunneled to the anterior chest wall, insertion site infection may give rise to a clinically evident soft tissue infection. Bacteremia due to S. aureus is common in this setting and continues to be the most dread form of CRS associated with entry site infection [13].
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Experimental data suggest that bacterial migration along the catheter tract is rapid and facilitated by a capillarity phenomenon [1]. Other microorganisms such as E. faecalis, P. aeruginosa or the enterobateriaceae can cause this type of infection, usually in patients with prolonged hospital stay or admitted to the intensive care unit whose normal skin flora has been replaced by the more virulent hospital acquired microorganisms. Exit site infection can usually be suspected by inspection: it often shows redness, induration and purulence. Microorganisms found in the blood and catheter tip can also be found at the entry site.
Endoluminal contamination (hub origin) This route of infection was suspected initially by scandinavian authors recommending heating of metallic hubs during manipulation of total parenteral nutrition catheters [14]. In the late 1970% and early eighties, CRS due to coagulase negative staphylococci became common in intensive care units [15] and epidemic in some parenteral nutrition units [16-18]. This happened without evidence of catheter skin entry site infection and despite the fact that adequate care was taken in catheter insertion and local catheter maintenance. A comprehensive microbiological protocol enabled us to trace the origin of these CRS to endoluminal contamination arising at the hub connecting the catheter with the giving set [19]. This finding allowed a better understanding of some previous observations not explainable by the traditional "skin hypothesis" [20]. Since then, hub contamination has been widely recognized as a precursor of CRS and represents the second or even first route of catheter contamination, depending, above all risk factors, on the mean catheterization time. The source of microorganisms reaching the catheter hub has not been investigated in depth but, most probably, bacteria are innoculated into the hub during its manipulation by the hands of the sanitary personnel [6]. From the beginning, it was clear hat hub related infections tended to appear during the second or third week after catheter insertion and were typically due to the coagulase negative staphylococci. The relatively late appearance of hub related CRS and, in consequence, its preferential association with T P N lines, has delayed appropriate recognition of the importance of endoluminal contamination. Most authors reporting a low frequency of hub contamination have investigated short-term (< 8 days) peripheral or central catheters. Thus, for reasons relating to the history of CRS and to the mean catheterization time, it has been argued that hub contamination is a particular feature of T P N catheters while, actually, it is not. All catheters requiring prolonged insertion, no matter for what purpose they are inserted, are susceptible of hub contamination. It is also worth noting that, although most endoluminal catheter infections are due to the coagulase negative
staphylococci, other microorganisms have been cultured from hubs such as: Proteus sp., Pseudomonas sp., S. aureus, Serratia rnarcescens and C. albicans [4, 6, 9, 10] reflecting the hospital flora potentially colonizing the hands of the personnel manipulating the catheter junction.
Mixed extraluminal and endoluminal contamination The culture patterns of endoluminal and extraluminal CRS have been clearly defined [5, 21] and it is usually possible to distinguish between the two if appropriate microbiological culture methods are employed. However, in some instances, the same microorganism is found at the insertion site, hub, tip and blood, and the actual origin of the infection remains controversial. These "mixed contaminations" may represent instances of endoluminal innoculation of microorganisms previously present on the patient's skin and transferred to the hub by nurses. Also, prolonged contact of an unprotected hub with the patient's own skin can facilitate bacterial growth around the connection and eventually its passage into the catheter lumen.
Hematogenous seeding and contamination of the infusate Hematogenous seeding of the intravascular catheter segment and contaminated infusates are rare causes of CRS, accounting probably for less than 10 p. 100 of all CRS episodes. They also have well defined microbiological culture patterns (Table II). There are no reports on the pathogenesis of hematogenous catheter seeding and in most series it is reported anecdotically. If other routes are minimized, extrinsic infusate contamination particularly if all-in-one T P N mixtures are employedmay be a source of concern as shown in our recent experience [10]. In fact, few studies have investigated the true incidence of CRS due to infusate contamination since in most reports dealing with CRS, cultures of the infusate have not been performed.
Table II Diagnosis of the origin of CRS (tip and blood for the same microorganism) according to culture patterns
CRS origin
Infusate
Hub
Skin
Distant focus Blood
Endoluminal
-
+
-
-
+
Extraluminal
-
-
+
-
+
Mixed
-
+
+
-
+
Infusate
+
-
-
+
Seeding
-
-
+
+
+ / -
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Implications for the diagnosis of catheter sepsis
The definitive diagnosis of CRS lies in the recovery of the same organism in catheter segments and blood. Brun-Buisson et coll. [22] have coined the term of non-bacteremic CRS for suspected CRS without isolation of microorganisms in the blood. As stated above, this is controversial and most authors would not accept the diagnosis of intravascular device related sepsis without a blood culture positive for the same organism recovered on the device. However, there is some disgreement about the catheter culture methods which best correlate with blood cultures and about the segments of the catheter that require culture. This arises mainly because the yield of a given culture method may be related to the route of contamination. The next paragraphs will focus on the relevance of the route of contamination to the results of the different tests commonly employed in microbiological laboratories. 1) The semiquantitative tip rolling method [23] is widely employed and, when CRS happens, the catheter tip usually yields more than 15 c.f.u, of the infecting organism. With this method only the outer surface of the catheter tip is cultured and, for that reason, it may give false negative results (< 15 c.f.u.) in some instances of CRS arising from the hub. This has been demonstrated both clinically and experimentally [3, 4, 24]. Furthermore, the predictive positive value of this culture method increases in direct proportion to the mean catheterization time [24]. 2) The relative superiority of central vs. peripheral quantitative blood cultures may also depend on the route of infection. Essentially, a quantitative culture of blood drawn through the catheter is a reverse endoluminal catheter culture similar to that proposed by Cleri and modified by Lifiares et al. [4, 25]. In consequence, its results will depend on the presence and the extent of endoluminal contamination. In our opinion, the final issue as to whether cultures of blood drawn through the catheter are superior to peripheral blood cultures depends mainly on the route of catheter contamination [26]. It is probable that in CRS due to hub contamination, central blood cultures are of diagnostic value whereas if the catheter is mostly contaminated on its outer surface, the number of c.f.u, obtained by the two techniques may not be that different. For these reasons, we feel that a simple gram stain and a qualitative hub culture serve better the purpose of detecting significant endoluminal contamination and hub related CRS than the more sophisticated and potentially risky central quantitative blood culture. It has the additional advantage of allowing "in situ" diagnosis of catheter sepsis [10]. 3) Culture methods devised to obtain the maximum yield of microorganisms from the catheter tip R#an. Urg., 1994,
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may be the ones correlating best with blood cultures. Vortexing or sonication of catheter tips immersed in sterile water or broth and posterior plating on agar, as described by Brtm-Buisson [27] and Sheretz et coll. [28], may be the quantitative methods of choice to detect significant endoluminal and/or extraluminal tip contamination. For this reason, they may better correlate with blood cultures than the semiquantitative method. 4) The more widespread use of culture swab of the inner surface of the hub will undoubtedly help much in the diagnosis of CRS, both before and after catheter removal. If the semiquantitative tip culture is negative, a hub culture, positive for the same microorganism isolated from blood, will lead to the correct diagnosis of CRS in almost 100 p. 100 of cases [10, 29]. Although quantitative hub cultures were useful to investigate the pathogenesis of endoluminal CRS [4, 19] its advantage in daily clinical practice remains controversial. We have obtained excellent results with a conventional swab qualitative culture since, usually, in hub related CRS, bacterial growth is confluent. Surveillance -three times a week- hub cultures were used by Salzman et al. [9] to investigate the natural history and prevalence of hub-originated CRS. Their results suggest that this type of routine cultures should be implemented in units with a high prevalence of suspected hub contamination or CRS in order to monitor preventive measures. However, if hubs are appropriately protected, surveillance cultures are almost always negative. This has resulted in our abandoning routine swab cultures in favor of selective hub gram stain and culture when CRS is suspected [10].
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Implications for the prevention of catheter sepsis
The disappearance of CRS largely depends on preventing bacteria to gain access to the catheter." Thus, according to the previous discussion, the crucial points for this are the following: 1) aseptic insertion and maintenance of the skin entry site; 2) hub protection and aseptic handling of the hub during its manipulation; 3) prevention of exlxiusic infusate contamination by preparing intravenous nlixtures in appropriate conditions; 4) preventing and treating bacteremias from other sources which may potentially seed the catheter. For the practicing clinician, the most important meastires that need to be taken to prevent CRS are those concerning the skin entry site and the hub. Prevention of extraluminal contamination
The most important single step for preventing CRS is aseptic catheter insertion [30] since most skin-
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related CRS, as occurs with surgical wound infections, appear within the first week of the procedure. The skin and the insertion field must be prepared as for a surgical intervention. The skin should be scrubbed with an antiseptic which should be left in situ for the required time. The person doing the insertion must do a surgical hand scrub and use sterile gloves. The value of gown, cap and mask is not proven but minimizes the chances of extrinsic contamination of the puncture site. The technical expertise of the nurse or doctor inserting the catheter also influences the incidence of CRS since, as with any clean surgical procedure, the amount of tissue trauma and the duration of the operation are directly related to the rate of wound infections. Probably, the only other single measure useful to prevent skin related CRS is the use of an antiseptic to keep the puncture sterile. There are other measures proposed to decrease skin-related CRS but none of them has found wide acceptance. There are no hard data to support the usefulness of long subcutaneous tunnels [31, 32]. The value of silver impregnated cuffs [33] to prevent CRS is controversial since in short term catheterization the incidence of bacteremia is rather low, and the cost-benefit of these devices is not clear; on the other hand, in catheters inserted for more than one week, the hub becomes the most relevant portal of entry for microorganisms and the cuffs are useless. Recent papers [34, 35] have shown the failure of these silver impregnated cuffs to prevent bacteremia in longterm central venous catheters. Maintaining the sterility around the catheter entry site, particularly during the first days after insertion, is also important. An antiseptic should be applied to the skin entry site; clorhexidine and providone are the best choice. So far, transparent dressings do not offer a clear-cut advantage over sterile gauze and tape [36]. Dressings of catheter and replacement of the giving set should be done whenever required, but twice a week routine changes appear safe enough [37] and may decrease the likelihood of hub contamination.
Prevention of endoluminal contamMation. Hub protection The single most important recent advance in the prevention of CRS, has been the recognition that appropriate hub protection can significantly reduce the rate of CRS [38, 40]. Different approaches have been t a k e n to protect the hub from exogenous contamination. The manipulation of the cathetergiving set ]unction must be done with extreme aseptic care to avoid the transfer of bacteria from the hands of the person handling the catheter to the hub. Thus, the use of sterile gloves during connection and disconnection maneuvers is mandatory. These maneuvers should be kept to a minimum in order to maintain the system as closed as possible.
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A major re-design effort must be done by compa, nies manufacturing catheters in order to implement them with safer hubs. The conventional Luer-lock type of connector was not designed to afford appropriate antibacterial protection, therefore, the hubs should be covered with a dressing imbedded in an atiseptic to minimize external contamination while in use. In our laboratory, studies have been carried out to test a new hub model consisting of an antiseptic chamber that protects the inner catheter surface from exogenous contamination. Experimental in vitro and in vivo studies [3, 41] have shown that purposeful contamination of the needle connecting the giving set with the catheter lumen does not result in endoluminal bacterial seeding. Initial clinical trials are showing promising results. Thus, the next generation of catheter hubs will have to take into account the relevance of endoluminal catheter contamination. It will also help to reduce the costs of junction manipulation since efficient "antibacterial hubs" will make aseptic handling of junctions and cumbersome external appliances a thing of the past.
References [1] COOPERG.L., SHILLER A.L., HOPKINS C.C. - - Possible role of capillary action in pathogenesis of experimental catheterassociated dermal tunnel infections. J. Clin. MicrobioL, 1988, 26, 8-12. [2] MERLINO R., GAILLARD J.L., FAUCHERREJ.L., CHAUMONT P., DRoY-LEFAIX MT., DESCAMPSP., RICOURC., VERON M. --- In vitro quantitative model of catheter infection during simulated parenteral nutrition. J. Clin. Microbiol., 1988, 26, 1659-1664. [3] SEGURA M., ALiA C., OMS L., VALVERDE J., FRANCR G., TORRES-RODRiGUEZJ,M., SITGES-SERRAA. - - Assessment of a new hub design and the semiquantitative catheter culture method using an in vivoexperimental model of catheter sepsis. J. Clin. Microbiol., 1990, 28, 2551-2554. [4] LI~ARES J., SITGES-SERRAA., GARAU J., PI~REZJ.L., MARTIN R. - - Pathogenesis of catheter sepsis: a prospective study with quantitative and semiquantitative cultures of catheter hub and segments. J. Clin. Microbiol., 1985, 21, 357-360. [5] FAN S.T., TEOH-CHAN C.H., LAU K.F., CHU K.W., KWAN A.K.B., WONG K.K. - - Predictive value of surveillance skin and hub cultures in central venous catheter sepsis. J. Hosp Infection, 1988, 12, 191-198. [6] Cicco M., PANARELLOG., CHIARADIAV., FRACASSOA., VERONESI A., TESTA V., SANTINI G., TESIO F. - - Source and route of microbial colonisation of parenteral nutrition catheters. Lancet, 1989, 2, 1258-1260. [7] WEIGNTMAN N.C., SIMPSON E.M., SPELKLER D.C.E., MOTT M.G., OAKHILLA. - - Bacteraemia related to indwelling central venous catheters: Prevention, diagnosis and treatment. Eur. J. Clin. MicrobioL, 1988, 7, 125-129. [8] CERCENADOE., ENA J., RODRIGUEZ-CRI~IXEMSM., ROMERO I., BOUZA E. - - A conservative procedure for the diagnosis of catheter-related infections. Arch. Int. Med., 1990, 150, 1417-1420. [9] SALZMAN M.B., ISENBERG H.D., SHAPIRO J.F., LIPSlTZ P.J., RUBIN L.G. - - A prospective study of catheter hub as the portal of entry for microorganisms causing catheter-related sepsis in neonates. J. Inf. Dis., 1993, 167, 487-490. [10] SEGURAM., LLAOOL., GUlRAOX., PIRACIESM., HERMS R., ALiA C., SITGES-SERRAA. ~ A prospective study of a new protocol for in situ diagnosis of central venous catheter related bacteraemia. Clin. Nutr., 1993, 12, 103-107.
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[11] CRANE Ch. - - Venous interruption for septic thrombophlebitis. N. Engl. J. Med., 1960, 262, 947-951. [12] MAKI D.C. - - Infections due to infusion therapy. In "Hospital Infections", Bennett J.V. and Brachman P.S. (Eds.), Little, Brown and Co, Boston, 1992, pp. 849-898. [13] RAAD 1., NARRO J., KHAN A., TARRAND J., VARTIVARIAN S., BODEY G.P. - - Serious complications of vascular catheterrelated Staphylococcus aureus bacteremia in cancer patients. Fur. J. Clin. MicrobioL INfect. Dis., 1992, 11, 675-682. [14] HOLM I., WRETLIND A. - - Prophylaxis against the infection and septicemia in parenteral nutrition via central intravenous catheter. Acta Chit. Scand., 1975, 141, 173-181.
[28] SHERETZR.J., RAAD II, BELANIA., Koo L.C., RAND K.H., PICKE'FF D.L., STRAUB S . A . , FAUERBACH L.L. - - Three-year experience with sonicated vascular catheters in a clinical microbiology laboratory. J. Clin. Microbiol., 1990, 28, 76-82. [29] HELLO J., GATELE J.M., ALMIRALE J., CAMPISTOLJ.M., GONZALEZ J., PUlG DE LA BELLACASAJ. - - Evaluation of culture techniques for identification of catheter-related infection in [30]
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[15] FORSE R.A., DIXON C., BERNARD K., MARTiNEZ L., McLEAN
A.P.H., MEAKINS J . L . , - Staphylococcus epidermidi~. An important pathogen. Surgery, 1979, 86, 507-514. [16] SlTGES-SERRAA., PUIG P., JAURRIETA E., GARAU J., ALASTRUE A., SlTGES-CREUSA. - - Catheter sepsis due to Staphylococ-
cus epidermidis during parenteral nutrition. Surg. GynecoL Obstet, 1980, 151, 481-483. [17] DEITEL M., KRAJDEN S., SALDANHAC.F., GREGORYW.D., FUSA M., CANTWELL E. - - An outbreak of Staphylococcus epidermidis septicemia. JPEN, 1983, 7, 569-572. [18] PEMBERTONL.B., LYMAN B., VANDAL J., COVINSKYJ. - - Outbreak of Staphylococcus epidermidis infections in patients receiving total parenteral nutrition. JPEN, 1984, 8, 325-326. [19] SlTGES-SERRAA., PUIG P., LI~'IARESJ., PEREZ J.L., FARRER0 N., JAURRIETA E., GARAU J. - - Hub colonization as the initial step in an outbreak of catheter-related sepsis due to coagulase negative staphylococci during parenteral nutrition. JPEN, 1984, 8, 668-672.
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[20] SITGES-SERRA A., LI£ARES L., GARAU J. - - Catheter sepsis:
the clue is the hub. Surgery, 1985, 97, 355-357. [21] SEGURA M., SlTGES-SERRA A. - - Intravenous catheter sites and sepsis. Lancet, 1991, 338, 1218.
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sepsis. Critical level of quantitative tip cultures. Arch. Int. Med., 1987, 147, 873-877. MAKI D.C., WEISE C.E., SARAFIN H.W. - - A semiquantitative culture method for indentifying intravenous-catheter-related infections. N. Engl. J. Med., 1977, 296, 1305-1309. SITGES-SERRA A., LII~ARESJ. - - Limitations of semiquantitative method for catheter culture. J. Clin. MicrobioL, 1988, 26, 1074. CLERI D.J., CORRADO M.L., SELIGMAN S.J. - - Quantitative culture of intravenous catheters and other intravascular inserts. J. Infect. Dis., 1980, 141,781-786. LI~ARESJ., SlTGES-SERRAA. - - Quantitative blood cultures for catheter-associated infections. J. Clin. Microbiol., 1990, 28, 1487-1488. BRUN-BuISSON C., ABROUK F., LEGRAND P., HUET Y., LARABI S., RAPIN M. - - Diagnosis of central venous catheter-related sepsis. Arch. Int. Med., 1987, 147, 873-877.
mmm
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hemodialysis patients. Fur. J. Clin., Microbiol Infect. Dis., 1989, 8, 620-622. BERNARDR.W., STARE W.M., CHASE R.M. - - Subclavian vein catheterizations: a prospective study. I1. Infectious complications. Ann. Surg., 1971, 173, 191-200. SITGES-SERRA A., LI~ARES J. - - Tunnels do not protect against venous-catheter-related sepsis. Lancet, 1984, 1, 459-460. MEYENFELDTM.M.F., STAPERTJ., DE JONG P.C.M., SOETERS P.B., WESDORP R.I.C., CREEPJ.M. TPN catheter sepsis: lack of effect of subcutaneous tunneling of PVC catheters on sepsis rate. JPEN, 1980, 4, 514-517. MAKI G., COBB L., CARMAN J.K., SHAPIRO J.M., RINGER M., HEEBERSON R . B . - - An attachable silver-impregnated cuff for prevention of infection with central venous catheters: a prospective study. Am. J. Med., 1988, 85, 307-314.
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[41 ]
attachable subcutaneous cuff for preventing triple lumen catheter infections in critically ill surgical and trauma patients. Surg. GynecoL Obstet, 1992, 175, 33-38. GROEGERJ.S., LUCAS A.B., COlT D., LAQUAGLIA M., BROWN A.E., TURNBULEA. - - Exelby P. A prospective randomized evaluation of the effect of silver impregnated subcutaneous cuffs for preventing tunneled chronic venous access catheter infections in cancer patients. Ann. Surg., 1993, 218, 206-210. HOFFMANN K.K., WEBER D.J., SAMSA G.P., RUTALA W~ - Transparent polyurethane film as an intravenous catheter dressing: a meta-analysis of the infection risks. JAMA, 1992, 267, 2072-2076. SITGES-SERRA, LII~ARESJ., PC:REZJ.L., JAURRIETA E., LORENTE L. - - A randomized trial on the effect of tubing changes on hub contamination and catheter sepsis during parenteral nutrition. JPEN, 1985, 9, 322-325. STO'FFERA.T., WARD H., WATERFIEEDA.H., HILTONJ., SIM A.J. - - Junctional care: The key to prevention of catheter sepsis in intravenous feeding. JPEN, 1987, 11, 159-162. HALPIN D.P., O'BYRNE P., MAENTEE G., HENNESSY ThPJ, STEPRENS R.B. - - Effect of a betadine connection shield on central venous catheter sepsis. Nutrition, 1991, 7, 33-34. INDUEY., NEZU R., MATSUDA H., FuJII M., NAKAI S., WASA M., TAKAGI Y., OKADA A. - - Prevention of catheter-related sepsis during parenteral nutritiont effect of a new connection device. JPEN, 1992, 16, 581-585. SEGURAM., ALiA C., OMS El, SANCHOJ.J., TORRESRODRiGUEZ J.M., SITGES-SERRAA. - - In vitro bacteriological study of a new hub model for intravascular catheters and infusion equipment. J. Clin. Microbiol., 1989, 27, 2656-2659.
In few other diseases is pathogenesis as relevant for diagnosis and prevention as is the case of catheter related sepsis (CRS). Many of the so called "controversial issues" in the field of CRS are good examples of misunderstandings arising from partial knowledge of the mechanisms whereby microorganisms gain access to the infusion system. Questions such as the value of a particular culture method, or the "in situ" diagnosis of CRS, or the relative merits of different preventive measures, can only be soundly approached once the pathogenesis of CRS is correctly understood. The aim of the present article is to describe the routes of catheter contamination and the implications that these have for correct micro-biological diagnosis and prevention of CRS.
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Pathogenesis of catheter related sepsis
Blood seeding of bacteria coming from an intravascular catheter is the end result of a complex process involving: 1) contamination of the catheter, 2) adherence of microorganisms to the internal and/or external surfaces of the catheter, 3) bacterial growth and 4) passage to the bloodstream. Each of these steps is now the object of separate studies thanks to the experimental models recently described [1, 3] which have shed much light on the intimate mechanisms underlying CRS. A brief summary of these steps is presented and a more thorough discussion on the clinical implications of the routes of catheter contamination will be discussed separately. Catheter contamination
Bacteria gain access to an intravascular catheter through four main routes: from the skin insertion site Hospital Universitari del Mar, Barcelona, Spain. * Department of Surgery and Infection Control. Correspondence to: Prof. A. Sitges-Serra, M.D., Department of Surgery, Hospital Universitari del Mar, Passeig Madtim, 25-29, 08003 Barcelona (Spain).
(puncture or cutdown), from the hub connecting the catheter with the giving set, from a contaminated infusate and from hematogenous seeding during bacteremias arising from a distant focus. Briefly, catheters get contaminated through the endoluminal or the extraluminal route. Adherence of microorganisms to catheter surfaces
After bacteria gain access to the intravascular device, it is thought that they adhere and replicate on catheter surfaces before they pass into the bloodstream in significant numbers [2]. In "in vivo" experimental studies [3], purposeful endoluminal contamination of catheters with S. warnerii was not always followed by bacterial adherence to the catheter and CRS, whereas catheters innoculated with Pseudomonas aeruginosa gave always rise to positive blood cultures and sepsis symptoms. In a report from a neonatal intensive care unit, recovery of certain species (Propionibacterium acnes, coagulase negative staphylococci) from surveillance hub cultures did not always result in CRS [4]. Thus, several factors play a role in determining bacterial adherence such as the species and strains of bacteria involved, slime production, catheter material and the type of infusate [2]. Growth of bacteria on the catheter
Bacterial adherence is followed by bacterial replication, extensive contamination of the catheter surfaces and progressively increasing seeding of microorganisms [2]. In hub related CRS the whole internal and much of the external catheter surfaces appear to be contaminated as shown by polysegmental endo and extraluminal catheter cultures [5]. According to most bacteriological studies on CRS, a critical number of bacteria contaminating the tip seems to be a prerequisite for a clinically relevant passage of bacteria to the bloodstream. R#an. Urg., 1994, 3 (3 bis), 359-364
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Bacteremia
microorganisms involved [3]. The magnitude of the innoculum and the route of infection may also be relevant but these have not been investigated in depth. Clinical experience suggests that extraluminal contamination occuring at the time of catheter insertion may lead to CRS within three to ten days.
This is the final step of CRS and gives rise to the first symptoms of the disease. Up to the present, a positive blood culture is considered to be a requisite to ascertain the diagnosis of CRS and it is generally thought that central venous catheters cannot be the source of fever in the absence of bacteremia. Bacteremia supervenes once a critical level of bacteria is surpassed, and, consequently, no matter what is the route of catheter contamination, bacteremia is always associated with a significant bacterial growth at the catheter tip. Authors using quantitative catheter cultures have defined a critical level for bacteria recovered (usually 1,000 c.f.u./mL of culture broth) to separate the concepts of "catheter infection" -with bacteremia- as opposed to "catheter colonization", not associated with clinical symptoms. These are useful concepts but, unfortunately, lack of knowledge about the relevance of endoluminal bacterial growth has created some misunderstanding about the relative value of the different culture methods and their corresponding cut-off points for bacterial growth. It is not known how much time it may take for the whole process leading to CRS to develop. In fact, little is known about the natural history of CRS, since experimental models have only been recently available. Initial results from an in vivo model developed in our laboratory suggests that time between endoluminal catheter contamination and the appearance of symptoms may depend on the virulence of the
•
Routes of catheter contamination
In recent years, several papers have addressed the relative importance of the different routes of catheter contamination. The introduction of endoluminal hub cultures has helped to elucidate the epidemiology of the different mechanisms through which intravascular catheters are contaminated. Other issues facilitating the understanding of contamination mechanisms have been the recognition that catheterization time and the policy for catheter maintenance are relevant to the pathogenesis of CRS. Briefly, it can be stated that the two more relevant routes of catheter contamination are the extraluminal route, through which the microorganisms migrate from the insertion site to the catheter tip along its outer surface, and the endoluminal route, through which the microorganisms gain access to the inner catheter surface through the catheter hub. The relative importance of these two mechanisms is shown in table I, constructed from reports in which the microbiological patterns for different types of CRS [5] were appropriately recognized [4, 10]. Table I
Relative importance of different routes of contamination of intravascular catheters
Author Cercenado [8] Cicco [6] Salzman [91 Lit'iares [41 Fan [5] Weightman [7] Segura [10]
N Catheters
Cath. Time
N of CRS
Hub
Skin
Mixed
Other 1
139 109 113 22 156 42 400 4
8.6 days 18.2 days 23.9 days 20 days 15 days 114 days 23 days
53 2 6 28 20 11 11 24
12 3 21 14 1 8 9
30 3 7 2 4
8
3
5
2
2
4 4 3 3 8
1 Hematogenous seeding, infusate contamination, unknown. 2 Positive catheter tips. 3 Incomplete cultures. 4 Patients.
Extraluminal contamination (skin origin)
Crane [11] was the first to suggest that CRS was secondary to microorganisms creeping, from an infected insertion site to the bloodstream, along the catheter tract. Since then, much data have accumulated in favor of this route of contamination that continues to be the most relevant one for catheters inserted for less than a week [12]. Because of a poor skin preparation, defective surgical technique or inappropriate dressing of the fresh skin puncture, the R~an. Urg., 1994, 3 (3 bis), 359-364
wound gets contaminated at the time of catheter insertion usually with skin comensals: coagulase negative staphylococci or S. aureus. This develops into a subdermal infection spreading along the subcutaneous tract surrounding the catheter. If the catheter has been tunneled to the anterior chest wall, insertion site infection may give rise to a clinically evident soft tissue infection. Bacteremia due to S. aureus is common in this setting and continues to be the most dread form of CRS associated with entry site infection [13].
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Experimental data suggest that bacterial migration along the catheter tract is rapid and facilitated by a capillarity phenomenon [1]. Other microorganisms such as E. faecalis, P. aeruginosa or the enterobateriaceae can cause this type of infection, usually in patients with prolonged hospital stay or admitted to the intensive care unit whose normal skin flora has been replaced by the more virulent hospital acquired microorganisms. Exit site infection can usually be suspected by inspection: it often shows redness, induration and purulence. Microorganisms found in the blood and catheter tip can also be found at the entry site.
Endoluminal contamination (hub origin) This route of infection was suspected initially by scandinavian authors recommending heating of metallic hubs during manipulation of total parenteral nutrition catheters [14]. In the late 1970% and early eighties, CRS due to coagulase negative staphylococci became common in intensive care units [15] and epidemic in some parenteral nutrition units [16-18]. This happened without evidence of catheter skin entry site infection and despite the fact that adequate care was taken in catheter insertion and local catheter maintenance. A comprehensive microbiological protocol enabled us to trace the origin of these CRS to endoluminal contamination arising at the hub connecting the catheter with the giving set [19]. This finding allowed a better understanding of some previous observations not explainable by the traditional "skin hypothesis" [20]. Since then, hub contamination has been widely recognized as a precursor of CRS and represents the second or even first route of catheter contamination, depending, above all risk factors, on the mean catheterization time. The source of microorganisms reaching the catheter hub has not been investigated in depth but, most probably, bacteria are innoculated into the hub during its manipulation by the hands of the sanitary personnel [6]. From the beginning, it was clear hat hub related infections tended to appear during the second or third week after catheter insertion and were typically due to the coagulase negative staphylococci. The relatively late appearance of hub related CRS and, in consequence, its preferential association with T P N lines, has delayed appropriate recognition of the importance of endoluminal contamination. Most authors reporting a low frequency of hub contamination have investigated short-term (< 8 days) peripheral or central catheters. Thus, for reasons relating to the history of CRS and to the mean catheterization time, it has been argued that hub contamination is a particular feature of T P N catheters while, actually, it is not. All catheters requiring prolonged insertion, no matter for what purpose they are inserted, are susceptible of hub contamination. It is also worth noting that, although most endoluminal catheter infections are due to the coagulase negative
staphylococci, other microorganisms have been cultured from hubs such as: Proteus sp., Pseudomonas sp., S. aureus, Serratia rnarcescens and C. albicans [4, 6, 9, 10] reflecting the hospital flora potentially colonizing the hands of the personnel manipulating the catheter junction.
Mixed extraluminal and endoluminal contamination The culture patterns of endoluminal and extraluminal CRS have been clearly defined [5, 21] and it is usually possible to distinguish between the two if appropriate microbiological culture methods are employed. However, in some instances, the same microorganism is found at the insertion site, hub, tip and blood, and the actual origin of the infection remains controversial. These "mixed contaminations" may represent instances of endoluminal innoculation of microorganisms previously present on the patient's skin and transferred to the hub by nurses. Also, prolonged contact of an unprotected hub with the patient's own skin can facilitate bacterial growth around the connection and eventually its passage into the catheter lumen.
Hematogenous seeding and contamination of the infusate Hematogenous seeding of the intravascular catheter segment and contaminated infusates are rare causes of CRS, accounting probably for less than 10 p. 100 of all CRS episodes. They also have well defined microbiological culture patterns (Table II). There are no reports on the pathogenesis of hematogenous catheter seeding and in most series it is reported anecdotically. If other routes are minimized, extrinsic infusate contamination particularly if all-in-one T P N mixtures are employedmay be a source of concern as shown in our recent experience [10]. In fact, few studies have investigated the true incidence of CRS due to infusate contamination since in most reports dealing with CRS, cultures of the infusate have not been performed.
Table II Diagnosis of the origin of CRS (tip and blood for the same microorganism) according to culture patterns
CRS origin
Infusate
Hub
Skin
Distant focus Blood
Endoluminal
-
+
-
-
+
Extraluminal
-
-
+
-
+
Mixed
-
+
+
-
+
Infusate
+
-
-
+
Seeding
-
-
+
+
+ / -
R~an. Urg., 1994, 3 (3 bis), 359-364
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Implications for the diagnosis of catheter sepsis
The definitive diagnosis of CRS lies in the recovery of the same organism in catheter segments and blood. Brun-Buisson et coll. [22] have coined the term of non-bacteremic CRS for suspected CRS without isolation of microorganisms in the blood. As stated above, this is controversial and most authors would not accept the diagnosis of intravascular device related sepsis without a blood culture positive for the same organism recovered on the device. However, there is some disgreement about the catheter culture methods which best correlate with blood cultures and about the segments of the catheter that require culture. This arises mainly because the yield of a given culture method may be related to the route of contamination. The next paragraphs will focus on the relevance of the route of contamination to the results of the different tests commonly employed in microbiological laboratories. 1) The semiquantitative tip rolling method [23] is widely employed and, when CRS happens, the catheter tip usually yields more than 15 c.f.u, of the infecting organism. With this method only the outer surface of the catheter tip is cultured and, for that reason, it may give false negative results (< 15 c.f.u.) in some instances of CRS arising from the hub. This has been demonstrated both clinically and experimentally [3, 4, 24]. Furthermore, the predictive positive value of this culture method increases in direct proportion to the mean catheterization time [24]. 2) The relative superiority of central vs. peripheral quantitative blood cultures may also depend on the route of infection. Essentially, a quantitative culture of blood drawn through the catheter is a reverse endoluminal catheter culture similar to that proposed by Cleri and modified by Lifiares et al. [4, 25]. In consequence, its results will depend on the presence and the extent of endoluminal contamination. In our opinion, the final issue as to whether cultures of blood drawn through the catheter are superior to peripheral blood cultures depends mainly on the route of catheter contamination [26]. It is probable that in CRS due to hub contamination, central blood cultures are of diagnostic value whereas if the catheter is mostly contaminated on its outer surface, the number of c.f.u, obtained by the two techniques may not be that different. For these reasons, we feel that a simple gram stain and a qualitative hub culture serve better the purpose of detecting significant endoluminal contamination and hub related CRS than the more sophisticated and potentially risky central quantitative blood culture. It has the additional advantage of allowing "in situ" diagnosis of catheter sepsis [10]. 3) Culture methods devised to obtain the maximum yield of microorganisms from the catheter tip R#an. Urg., 1994,
3 (3 bis), 3 5 9 - 3 6 4
may be the ones correlating best with blood cultures. Vortexing or sonication of catheter tips immersed in sterile water or broth and posterior plating on agar, as described by Brtm-Buisson [27] and Sheretz et coll. [28], may be the quantitative methods of choice to detect significant endoluminal and/or extraluminal tip contamination. For this reason, they may better correlate with blood cultures than the semiquantitative method. 4) The more widespread use of culture swab of the inner surface of the hub will undoubtedly help much in the diagnosis of CRS, both before and after catheter removal. If the semiquantitative tip culture is negative, a hub culture, positive for the same microorganism isolated from blood, will lead to the correct diagnosis of CRS in almost 100 p. 100 of cases [10, 29]. Although quantitative hub cultures were useful to investigate the pathogenesis of endoluminal CRS [4, 19] its advantage in daily clinical practice remains controversial. We have obtained excellent results with a conventional swab qualitative culture since, usually, in hub related CRS, bacterial growth is confluent. Surveillance -three times a week- hub cultures were used by Salzman et al. [9] to investigate the natural history and prevalence of hub-originated CRS. Their results suggest that this type of routine cultures should be implemented in units with a high prevalence of suspected hub contamination or CRS in order to monitor preventive measures. However, if hubs are appropriately protected, surveillance cultures are almost always negative. This has resulted in our abandoning routine swab cultures in favor of selective hub gram stain and culture when CRS is suspected [10].
•
Implications for the prevention of catheter sepsis
The disappearance of CRS largely depends on preventing bacteria to gain access to the catheter." Thus, according to the previous discussion, the crucial points for this are the following: 1) aseptic insertion and maintenance of the skin entry site; 2) hub protection and aseptic handling of the hub during its manipulation; 3) prevention of exlxiusic infusate contamination by preparing intravenous nlixtures in appropriate conditions; 4) preventing and treating bacteremias from other sources which may potentially seed the catheter. For the practicing clinician, the most important meastires that need to be taken to prevent CRS are those concerning the skin entry site and the hub. Prevention of extraluminal contamination
The most important single step for preventing CRS is aseptic catheter insertion [30] since most skin-
Xll ~ Conference de Consensus en R6animation et M#decine d'Urgence -
related CRS, as occurs with surgical wound infections, appear within the first week of the procedure. The skin and the insertion field must be prepared as for a surgical intervention. The skin should be scrubbed with an antiseptic which should be left in situ for the required time. The person doing the insertion must do a surgical hand scrub and use sterile gloves. The value of gown, cap and mask is not proven but minimizes the chances of extrinsic contamination of the puncture site. The technical expertise of the nurse or doctor inserting the catheter also influences the incidence of CRS since, as with any clean surgical procedure, the amount of tissue trauma and the duration of the operation are directly related to the rate of wound infections. Probably, the only other single measure useful to prevent skin related CRS is the use of an antiseptic to keep the puncture sterile. There are other measures proposed to decrease skin-related CRS but none of them has found wide acceptance. There are no hard data to support the usefulness of long subcutaneous tunnels [31, 32]. The value of silver impregnated cuffs [33] to prevent CRS is controversial since in short term catheterization the incidence of bacteremia is rather low, and the cost-benefit of these devices is not clear; on the other hand, in catheters inserted for more than one week, the hub becomes the most relevant portal of entry for microorganisms and the cuffs are useless. Recent papers [34, 35] have shown the failure of these silver impregnated cuffs to prevent bacteremia in longterm central venous catheters. Maintaining the sterility around the catheter entry site, particularly during the first days after insertion, is also important. An antiseptic should be applied to the skin entry site; clorhexidine and providone are the best choice. So far, transparent dressings do not offer a clear-cut advantage over sterile gauze and tape [36]. Dressings of catheter and replacement of the giving set should be done whenever required, but twice a week routine changes appear safe enough [37] and may decrease the likelihood of hub contamination.
Prevention of endoluminal contamMation. Hub protection The single most important recent advance in the prevention of CRS, has been the recognition that appropriate hub protection can significantly reduce the rate of CRS [38, 40]. Different approaches have been t a k e n to protect the hub from exogenous contamination. The manipulation of the cathetergiving set ]unction must be done with extreme aseptic care to avoid the transfer of bacteria from the hands of the person handling the catheter to the hub. Thus, the use of sterile gloves during connection and disconnection maneuvers is mandatory. These maneuvers should be kept to a minimum in order to maintain the system as closed as possible.
363
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A major re-design effort must be done by compa, nies manufacturing catheters in order to implement them with safer hubs. The conventional Luer-lock type of connector was not designed to afford appropriate antibacterial protection, therefore, the hubs should be covered with a dressing imbedded in an atiseptic to minimize external contamination while in use. In our laboratory, studies have been carried out to test a new hub model consisting of an antiseptic chamber that protects the inner catheter surface from exogenous contamination. Experimental in vitro and in vivo studies [3, 41] have shown that purposeful contamination of the needle connecting the giving set with the catheter lumen does not result in endoluminal bacterial seeding. Initial clinical trials are showing promising results. Thus, the next generation of catheter hubs will have to take into account the relevance of endoluminal catheter contamination. It will also help to reduce the costs of junction manipulation since efficient "antibacterial hubs" will make aseptic handling of junctions and cumbersome external appliances a thing of the past.
References [1] COOPERG.L., SHILLER A.L., HOPKINS C.C. - - Possible role of capillary action in pathogenesis of experimental catheterassociated dermal tunnel infections. J. Clin. MicrobioL, 1988, 26, 8-12. [2] MERLINO R., GAILLARD J.L., FAUCHERREJ.L., CHAUMONT P., DRoY-LEFAIX MT., DESCAMPSP., RICOURC., VERON M. --- In vitro quantitative model of catheter infection during simulated parenteral nutrition. J. Clin. Microbiol., 1988, 26, 1659-1664. [3] SEGURA M., ALiA C., OMS L., VALVERDE J., FRANCR G., TORRES-RODRiGUEZJ,M., SITGES-SERRAA. - - Assessment of a new hub design and the semiquantitative catheter culture method using an in vivoexperimental model of catheter sepsis. J. Clin. Microbiol., 1990, 28, 2551-2554. [4] LI~ARES J., SITGES-SERRAA., GARAU J., PI~REZJ.L., MARTIN R. - - Pathogenesis of catheter sepsis: a prospective study with quantitative and semiquantitative cultures of catheter hub and segments. J. Clin. Microbiol., 1985, 21, 357-360. [5] FAN S.T., TEOH-CHAN C.H., LAU K.F., CHU K.W., KWAN A.K.B., WONG K.K. - - Predictive value of surveillance skin and hub cultures in central venous catheter sepsis. J. Hosp Infection, 1988, 12, 191-198. [6] Cicco M., PANARELLOG., CHIARADIAV., FRACASSOA., VERONESI A., TESTA V., SANTINI G., TESIO F. - - Source and route of microbial colonisation of parenteral nutrition catheters. Lancet, 1989, 2, 1258-1260. [7] WEIGNTMAN N.C., SIMPSON E.M., SPELKLER D.C.E., MOTT M.G., OAKHILLA. - - Bacteraemia related to indwelling central venous catheters: Prevention, diagnosis and treatment. Eur. J. Clin. MicrobioL, 1988, 7, 125-129. [8] CERCENADOE., ENA J., RODRIGUEZ-CRI~IXEMSM., ROMERO I., BOUZA E. - - A conservative procedure for the diagnosis of catheter-related infections. Arch. Int. Med., 1990, 150, 1417-1420. [9] SALZMAN M.B., ISENBERG H.D., SHAPIRO J.F., LIPSlTZ P.J., RUBIN L.G. - - A prospective study of catheter hub as the portal of entry for microorganisms causing catheter-related sepsis in neonates. J. Inf. Dis., 1993, 167, 487-490. [10] SEGURAM., LLAOOL., GUlRAOX., PIRACIESM., HERMS R., ALiA C., SITGES-SERRAA. ~ A prospective study of a new protocol for in situ diagnosis of central venous catheter related bacteraemia. Clin. Nutr., 1993, 12, 103-107.
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[11] CRANE Ch. - - Venous interruption for septic thrombophlebitis. N. Engl. J. Med., 1960, 262, 947-951. [12] MAKI D.C. - - Infections due to infusion therapy. In "Hospital Infections", Bennett J.V. and Brachman P.S. (Eds.), Little, Brown and Co, Boston, 1992, pp. 849-898. [13] RAAD 1., NARRO J., KHAN A., TARRAND J., VARTIVARIAN S., BODEY G.P. - - Serious complications of vascular catheterrelated Staphylococcus aureus bacteremia in cancer patients. Fur. J. Clin. MicrobioL INfect. Dis., 1992, 11, 675-682. [14] HOLM I., WRETLIND A. - - Prophylaxis against the infection and septicemia in parenteral nutrition via central intravenous catheter. Acta Chit. Scand., 1975, 141, 173-181.
[28] SHERETZR.J., RAAD II, BELANIA., Koo L.C., RAND K.H., PICKE'FF D.L., STRAUB S . A . , FAUERBACH L.L. - - Three-year experience with sonicated vascular catheters in a clinical microbiology laboratory. J. Clin. Microbiol., 1990, 28, 76-82. [29] HELLO J., GATELE J.M., ALMIRALE J., CAMPISTOLJ.M., GONZALEZ J., PUlG DE LA BELLACASAJ. - - Evaluation of culture techniques for identification of catheter-related infection in [30]
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A.P.H., MEAKINS J . L . , - Staphylococcus epidermidi~. An important pathogen. Surgery, 1979, 86, 507-514. [16] SlTGES-SERRAA., PUIG P., JAURRIETA E., GARAU J., ALASTRUE A., SlTGES-CREUSA. - - Catheter sepsis due to Staphylococ-
cus epidermidis during parenteral nutrition. Surg. GynecoL Obstet, 1980, 151, 481-483. [17] DEITEL M., KRAJDEN S., SALDANHAC.F., GREGORYW.D., FUSA M., CANTWELL E. - - An outbreak of Staphylococcus epidermidis septicemia. JPEN, 1983, 7, 569-572. [18] PEMBERTONL.B., LYMAN B., VANDAL J., COVINSKYJ. - - Outbreak of Staphylococcus epidermidis infections in patients receiving total parenteral nutrition. JPEN, 1984, 8, 325-326. [19] SlTGES-SERRAA., PUIG P., LI~'IARESJ., PEREZ J.L., FARRER0 N., JAURRIETA E., GARAU J. - - Hub colonization as the initial step in an outbreak of catheter-related sepsis due to coagulase negative staphylococci during parenteral nutrition. JPEN, 1984, 8, 668-672.
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[34] NORWOOD S., HAJJAR G., JENKINS L. - - The influence of an
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[20] SITGES-SERRA A., LI£ARES L., GARAU J. - - Catheter sepsis:
the clue is the hub. Surgery, 1985, 97, 355-357. [21] SEGURA M., SlTGES-SERRA A. - - Intravenous catheter sites and sepsis. Lancet, 1991, 338, 1218.
[36]
[22] BRUN BUISSON Oh., ABROUK F., LEGRAND P., HUET Y., LARABI S., RAPIN M. - - Diagnosis of central venous catheter-related
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[26] [27]
sepsis. Critical level of quantitative tip cultures. Arch. Int. Med., 1987, 147, 873-877. MAKI D.C., WEISE C.E., SARAFIN H.W. - - A semiquantitative culture method for indentifying intravenous-catheter-related infections. N. Engl. J. Med., 1977, 296, 1305-1309. SITGES-SERRA A., LII~ARESJ. - - Limitations of semiquantitative method for catheter culture. J. Clin. MicrobioL, 1988, 26, 1074. CLERI D.J., CORRADO M.L., SELIGMAN S.J. - - Quantitative culture of intravenous catheters and other intravascular inserts. J. Infect. Dis., 1980, 141,781-786. LI~ARESJ., SlTGES-SERRAA. - - Quantitative blood cultures for catheter-associated infections. J. Clin. Microbiol., 1990, 28, 1487-1488. BRUN-BuISSON C., ABROUK F., LEGRAND P., HUET Y., LARABI S., RAPIN M. - - Diagnosis of central venous catheter-related sepsis. Arch. Int. Med., 1987, 147, 873-877.
mmm
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hemodialysis patients. Fur. J. Clin., Microbiol Infect. Dis., 1989, 8, 620-622. BERNARDR.W., STARE W.M., CHASE R.M. - - Subclavian vein catheterizations: a prospective study. I1. Infectious complications. Ann. Surg., 1971, 173, 191-200. SITGES-SERRA A., LI~ARES J. - - Tunnels do not protect against venous-catheter-related sepsis. Lancet, 1984, 1, 459-460. MEYENFELDTM.M.F., STAPERTJ., DE JONG P.C.M., SOETERS P.B., WESDORP R.I.C., CREEPJ.M. TPN catheter sepsis: lack of effect of subcutaneous tunneling of PVC catheters on sepsis rate. JPEN, 1980, 4, 514-517. MAKI G., COBB L., CARMAN J.K., SHAPIRO J.M., RINGER M., HEEBERSON R . B . - - An attachable silver-impregnated cuff for prevention of infection with central venous catheters: a prospective study. Am. J. Med., 1988, 85, 307-314.
[37]
[36]
[39] [40]
[41 ]
attachable subcutaneous cuff for preventing triple lumen catheter infections in critically ill surgical and trauma patients. Surg. GynecoL Obstet, 1992, 175, 33-38. GROEGERJ.S., LUCAS A.B., COlT D., LAQUAGLIA M., BROWN A.E., TURNBULEA. - - Exelby P. A prospective randomized evaluation of the effect of silver impregnated subcutaneous cuffs for preventing tunneled chronic venous access catheter infections in cancer patients. Ann. Surg., 1993, 218, 206-210. HOFFMANN K.K., WEBER D.J., SAMSA G.P., RUTALA W~ - Transparent polyurethane film as an intravenous catheter dressing: a meta-analysis of the infection risks. JAMA, 1992, 267, 2072-2076. SITGES-SERRA, LII~ARESJ., PC:REZJ.L., JAURRIETA E., LORENTE L. - - A randomized trial on the effect of tubing changes on hub contamination and catheter sepsis during parenteral nutrition. JPEN, 1985, 9, 322-325. STO'FFERA.T., WARD H., WATERFIEEDA.H., HILTONJ., SIM A.J. - - Junctional care: The key to prevention of catheter sepsis in intravenous feeding. JPEN, 1987, 11, 159-162. HALPIN D.P., O'BYRNE P., MAENTEE G., HENNESSY ThPJ, STEPRENS R.B. - - Effect of a betadine connection shield on central venous catheter sepsis. Nutrition, 1991, 7, 33-34. INDUEY., NEZU R., MATSUDA H., FuJII M., NAKAI S., WASA M., TAKAGI Y., OKADA A. - - Prevention of catheter-related sepsis during parenteral nutritiont effect of a new connection device. JPEN, 1992, 16, 581-585. SEGURAM., ALiA C., OMS El, SANCHOJ.J., TORRESRODRiGUEZ J.M., SITGES-SERRAA. - - In vitro bacteriological study of a new hub model for intravascular catheters and infusion equipment. J. Clin. Microbiol., 1989, 27, 2656-2659.