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Coagulase-negative staphylococcal bacteraemia with special reference to septic shock: Experience in an intensive care unit
Journal oflnfectwn (1994) zg, 295-3o3
Coagulase-negative staphylococcal bacteraemia with special r e f e r e n c e to s e p t i c s h o c k : e x p e r i e n c e i n a n i n t e n s i v e c a r e u n i t N a b i l S. D a h m a s h , I M o h a m m e d N. H. C h o w d h u r y 2 a n d D e s o u k y F. F a y e d 3
Departments of 1Medicine, 2Microbiology, and aPharmacy, College of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia Accepted for publication IO May I994 Summary During a period of 4"5 years, 48 patients with bacteraemia due to coagulase-negative staphylococci were studied prospectively in order to evaluate their clinical profile, management and outcome. There were 25 males and 23 females with ages ranging between I3 and Ioo years. Over 60 ~/o of patients belonged to the age group 30 to 69 years. Shock was recorded in 23 (48 ~/o) of the 48 patients. Of the shocked patients, i6 were immunocompromised and also had abnormal coagulation. Their mortality was 44 %. By contrast, none of the immunocompromised patients without shock died. Abnormal coagulation was found in I7 patients without septic shock. Their mortality was 5"9 %. The commonest underlying disease was respiratory failure especially in shocked patients. The source of infection was identified in the majority of cases. In addition, most patients had an indwelling intravascular catheter especially an arterial one. The overall mortality was I6"7 % (8/48). It was significantly higher in patients with shock than in those without shock (30"4% vs. 4'0%, P < 0'05).
Introduction Coagulase-negative staphylococci ( C N S ) , previously regarded as harmless commensal, contaminant, or n o n - p a t h o g e n i c organisms, have emerged in recent years as serious pathogens among patients in hospital. 1-4 T h e r e has been a significant increase in the incidence of infection due to C N S and which has been attributed to recent advances in medical technology. T h e y are a major cause o f bacteraemia associated with intravenous catheters such as H i c k m a n catheters, central venous nutrition catheters, and peripheral intravenous catheters. 2'5,6 T h e y are also a significant cause of endocarditis, otitis media, peritonitis following dialysis, infection of prosthetic heart valves, joint prostheses and vascular shunts. 7 In addition, they have b e c o m e increasingly c o m m o n in patients with granulocytopenia and recipients of bone m a r r o w transplants2' 8 T h e s e infections m a y p r o v e fatal and also prolong the duration of patients' stay in hospital. 3 Although several reports a' 4.7 concerning the importance of bacteraemia due to C N S a m o n g patients in hospital have been published, little is k n o w n a b o u t septic shock in critically ill patients in an intensive care unit ( I C U ) 2 '4 T h e main p u r p o s e of this s t u d y was to report prospectively the incidence, coagulation profile, treatment, and mortality of septic shock due to C N S in the I C U at K i n g Khalid U n i v e r s i t y Hospital ( K K U H ) , Riyadh, Saudi Arabia. In Address correspondence to: Prof M. N. H. Chowdhury, P.O. Box 54803, Riyadh 11524, Saudi Arabia.
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addition, a comparison of various factors predicting mortality was made between these patients and those without septic shock. K K U H is a major teaching hospital which provides both primary and tertiary care. T h e I C U consists of six beds with all modern facilities. M a t e r i a l s and m e t h o d s
A total of 48 cases of CNS bacteraemia was investigated prospectively in the I C U at K K U H during a period of 54 months from January 1989 to August I993. A case of bacteraemia due to CNS was defined as a patient from whom any species of CNS was isolated from two or more blood culture bottles collected 48 hours after a patient's admission to the medical wards or I C U when clinical evidence of infection was present. Underlying diseases which preceded bacteraemia and/or septic shock were classified as rapidly fatal, ultimately fatal or non-fatal by means of criteria described earlier.9 In 16 cases, which were excluded from the study, other species of bacteria or fungi were isolated from the same sets of blood cultures. If a patient had more than one episode of bacteraemia due to CNS, only the first episode was used in the analysis. Blood cultures were collected from patients when bacteraemia and/or septic shock were suspected either in the medical wards or in the I C U as described previously by us. l°'n At least two sets of blood cultures were collected from each patient via peripheral venepuncture. Any species of CNS isolated from at least two different blood samples was considered as clinically significant. A single positive blood culture set was considered to indicate contamination. In cases of doubt, blood cultures were repeated in order to exclude any contamination. In addition, urine, sputum, and swabs from local catheter sites were collected simultaneously from these patients. Cultures, including blood cultures, were also repeated during the course of illness especially at any time when a patient's condition deteriorated. CNS were detected by means of negative coagulase and DNAase tests. T h e y were further identified to species level by use of the API system (Balme Les Grothes 3839o, Montalieu Vaarieu, France). Antibiotic susceptibility was determined by means o f disc diffusion and use of the rotating Stoke's technique) 2 Methicillin susceptibility was determined by means of methicillin strips (25#g) obtained from Mast Laboratories (Bootle, Merseyside, U.K.) and use of salt-agar at 37 °C. Both methicillin sensitive and resistant strains were included with each set of sensitivity plates as controls. 12 Septic shock was defined as a decrease in systolic blood pressure to < 9o m m H g or a 7o m m H g decrease in systolic or diastolic pressure in patients with previously stable hypertensive values. '3'~ In addition, there was progressive deterioration of cellular and tissue perfusion leading to severe metabolic derangement and organ failure in patients with septic shock due to overwhelming infection with CNS. Patients were evaluated on admission to the I C U as regards age, sex, primary diagnosis, presence of indwelling catheters, signs and symptoms, underlying disease, preceding infection, pertinent laboratory data and antibiotic sensitivities as well as antibiotics used before and during septic episodes. Fever, leucocytosis and leucopenia were
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defined in accordance with previous publications. 11'1~ A source of infection was identified when isolates from sites of inflammation matched with those from blood cultures. H It was deemed advisable to establish whether these isolates were identical or not. This was done by identifying the organisms by means of the API system (Balme Les Grothes 38390, Montalieu Vaarieu, France) and also by antibiotic susceptibility pattern. In addition, most patients were observed to have inflammation at the localised site of infection. Molecular and phage typing was not done. All catheters, including arterial catheters, central venous pressure monitoring lines, and Swan-Ganz catheters, were removed and cultured quantitatively according to the method of Cleri et al./5 when clinical evidence suggested bacteraemia. Each catheter tip was washed and flushed through with 2 ml sterile broth. T h e broth was then diluted Ioo-fold and a measured amount cultured on blood and MacConky agars. T h e number of colonyforming units (CFU) per catheter was calculated. A growth of > Iooo C F U was regarded as indicating infection while a growth of < Iooo C F U was considered as indeterminate, probably the result of contamination or indicating an early stage of colonisation. None of the arterial catheters remained in place for more than 4 days. After removal of intravascular catheters, patients were monitored closely. Antibiotics were administered empirically to patients who continued to have clinical evidence of bacteraemia such as persistent fever, leucocytosis and hypotension. T r e a t m e n t was modified, if necessary, as soon as results of the susceptibility of CNS isolated were obtained. In addition to antibiotic treatment, patients with shock received fluid in the form of crystalloids or colloids. Vasopressor drugs were added if there was no response to fluid therapy. 11 Swan-Ganz catheters were inserted in four patients with septic shock and who had a transient response to the administration of fluid. 1~ T h e duration of stay of patients with bacteraemia without shock ranged between 5 and 95 days (mean = I9"8 days) and for those with septic shock between 2 and I25 days (mean = 34"4 days). All patients were followed in the I C U until full recovery or death. Statistical analysis
For comparison among groups, the X2 test and Fisher's exact test were used. P < 0"05 was considered to be significant. Results
A total of 48 patients had bacteraemia due to CNS. Most (35/48) of the infections were acquired in the ICU, while 27 % (I3/48) were acquired in the medical wards. Table I shows the clinical and demographic data of 48 patients of whom 48 % (23/48) met the criteria for septic shock. T h e y included Io males and I3 females, their ages ranging from I6 to 8o years (mean = 53"7 years). T h e r e were I5 male and IO female patients without septic shock with ages ranging from I3 to IOO years (mean = 47"5). T h e r e was no significant difference in mortality between the sexes and among the various age groups. Most patients with and without septic shock had fever and leucocytosis. Among patients with
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T a b l e I Clinical and demographic data of patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Variable Age (years) 13 - 2 9 3o--49 50-69 > 7o Total Sex Male Female U n d e r l y i n g disease NF RF UF Fever > 37"8 °C 36-37"8 °C < 36 °C
L e u c o c y t e c o u n t ( x lO9/1) > II'O 4"o-11 < 4"0 Mechanical ventilation Yes No Steroids/Immune suppression Yes No
No.
Bacteraemia Died (%)
7 6 8 4 25
o I o o I
15 IO
No.
Septic shock Died (%)
2 8 7 6 23
I o 3 3 7
o I
IO 13
3 4
5 6 14
o o i
I 6 16
o 2 5
16 8
o i
13 5
4 I
I
o
5
2
15 6 4
o I O
16 5 2
5 2 O
19 6
o I
2o 3
6 i
15 IO
o
16 7
7 o
(4"0)
(7"1)
I
(I0"O)
(30'4)
(33"3) (31"2 )
(43'8)
N F = n o n - f a t a l , R F = rapidly fatal, U F = u l t i m a t e l y fatal.
T a b l e II Mortality related to underlying disease in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Disease R e s p i r a t o r y failure Cerebrovascular accident Diabetes mellitus H e p a t i c failure R e n a l failure Vasculitis Leukaemia/lymphoma/malignant neoplasia Miscellaneous Total
No.
Bacteraemia Died (%)
No.
Septic shock Died (%)
6 4 3 3 I I 5
I o o o o
iz 4 z I I
O
2
I
o
I
o
2
o
o
o
25
I
23
7
(4"0)
3 2 o o 1
(30'4)
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Table I I I Results of coagulation tests in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Variable Normal coagulation Abnormal coagulation DIC Others
No.
Bacteraemia Died (%)
8
o
z I5
o I
(6'7)
No.
Septic shock Died (%)
7
o
2 14
z 5
(Ioo) (35'7)
DIC = Disseminated intravascular coagulation. septic shock, no significant difference in mortality was noted between those being mechanically ventilated and those not being mechanically ventilated (3o 0/0 vs. 3o'3 %, P > o'o5). Most patients with septic shock were i m m u n o compromised, due either to disease or because they were receiving i m m u n o suppressive drugs. T h e i r mortality was 4 4 % compared to o % mortality among patients who were not i m m u n o c o m p r o m i s e d . (P < o'o5). By contrast, none of the patients without septic shock and who were either receiving ventilatory support or were i m m u n o c o m p r o m i s e d , died. T h e overall mortality of patients with septic shock was 3o'4 % compared to 4"o % mortality among patients without septic shock (P < o'os). Table II shows the underlying diseases and mortality among the 48 patients. Respiratory failure (37"5~o) was the most c o m m o n underlying clinical condition. Of the 48 patients, 39 were being mechanically ventilated. T h e indication for mechanical ventilation was acute respiratory failure secondary to p u l m o n a r y disease in I8 patients. In the remaining 2I patients, mechanical ventilation was required for various reasons including coma as a result of cerebrovascular accident (eight patients), hepatic failure (four patients), progressive lung infiltrates associated with vasculitis (three patients) and malignant haematologic neoplasia (6 patients). Six of the 39 patients died of septic shock. Table I I I shows the results of coagulation tests in the 48 patients. A m o n g those with septic shock, coagulation was found to be normal in seven patients and abnormal in i6 patients. Prolongation o f p r o t h r o m b i n time (PT) was seen in three patients who survived. Prolongation of P T and partial thromboplastin time ( P T T ) was found in four patients while prolongation of P T and thrombocytopenia were found in another four patients with a mortality of o % and 5o %, respectively. Prolongation of P T , P T T , and thrombocytopenia was recorded in two patients, isolated thrombocytopenia in one patient and disseminated intravascular coagulation (DIC) in two patients with a mortality of ioo 0/0 for each group. In patients without septic shock, coagulation was found to be normal in eight patients and abnormal in z7. T h e latter included eight patients with prolonged P T , two with prolonged P T and P T T , two with prolonged P T and thrombocytopenia, two with prolonged P T , P T T , thrombocytopenia and two with D I C . T h r o m b o c y t o p e n i a alone was found in one patient who died. T h e patients with shock and coagulopathy had a higher
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T a b l e IV Sources of infection in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Source
No.
Total Died
Bacteraemia No. Died
Septic shock No. Died
Arterial catheter Swan-Ganz catheter Central venous catheter
33 2 6
2 o I
2o 2 3
I o o
I3 o 3
I o I
Femoral venous catheter Total catheter-associated
I 42
I 4
o 25
o I
I 17
I 3
Respiratory tract Other Unknown Total
I 3 9 55*
I o 3 8
o 2 2 29
o o o I
i I 7 26**
i o 3 7
* Seven patients had m o r e than one source of infection. ** T h r e e p a t i e n t s h a d m o r e t h a n o n e s o u r c e o f i n f e c t i o n .
mortality than those with coagulopathy b u t w i t h o u t shock (44 % vs. 6 %; P < 0"05). T a b l e IV shows the sources of infection which were identified in most of the patients. Arterial catheters were f o u n d to be the c o m m o n e s t source of infection. F o u r patients had a n o r m a l mental state at the time of septic shock, I6 patients were unresponsive and three sedated, with mortality of 25 %, 37"5 % and o %, respectively. A m o n g patients w i t h o u t septic shock, I I had a n o r m a l mental state while seven were sedated and seven were unresponsive. M o r t a l i t y a m o n g the last group was 20 %. Cultures obtained from blood, catheter sites and catheter tips a r o u n d the time of each patient's deterioration were positive for C N S . E x a m i n a t i o n of other specimens, however, did not reveal any pathogen at that time. O n l y six isolates of C N S were sensitive to methicillin. T h e y included five isolates from patients w i t h o u t septic shock and one f r o m patients with septic shock. All isolates were sensitive to vancomycin. Catheters were r e m o v e d from all patients. Only in seven patients did bacteraemia remit following this procedure. A m o n g the remaining patients, six were treated with cloxacillin and 35 with vancomycin. Discussion
A l t h o u g h bacteraemia caused by C N S is not u n c o m m o n , septic shock due to C N S has rarely been reported. 3'~' 11 T h i s is probably the first comprehensive report o f septic shock due to C N S . Ponce and Wenzel 4 in a study of IO8 episodes of bacteraemia due to C N S in IOO patients over a 7-year period at the University of Virginia Medical Center, n o t e d septic shock in 22 % of their patients. Similarly, M a r t i n et al) f o u n d evidence o f septic shock in I 7 % ( 2 o / I I 8 ) of their patients with bacteraemia due to C N S . T h e y also reported an incidence of I7"5 % for h y p o t e n s i o n in their patients with a single positive blood culture compared to I7 % in patients with two or more positive blood cultures. A striking finding
Staphylococcal bacteraemia
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of the present survey was the high incidence of shock (48 %) in our patients. This high incidence is probably due to the fact that these patients were seriously ill requiring admission to the I C U and intensive management. Until recently, shock was rarely mentioned in reviews of bacteraemia caused by organisms other than Gram-negative bacilli. All of our patients were over the age of 13 years and most of the infections were acquired in the ICU. By contrast, in other studies, 3'4 a significant n u m b e r of patients were premature infants or patients in paediatric or surgical intensive care units. T h e isolation of CNS from blood often presents the clinical microbiologist with the difficult task of deciding if this reflects true bacteraemia or contamination from the skin. Kirchhoff and Sheagren 16 considered CNS to be true blood pathogens in patients with intravascular devices for whom (I) a high proportion of blood cultures were positive for this organism over a short period of time, (2) cultures became positive in less than 48 hours with a high percentage of both bottles being positive. Recently, Martin et al. 3 found that 40 patients with bacteraemia due to CNS had a single positive blood culture whereas 78 had two or more positive blood cultures. In our series, all patients had genuine CNS bacteraemia since it was confirmed by isolation of the organism from different, multiple sets of blood samples. Most of our cultures were also positive within 48 hours. In addition, patients presented with the clinical features of bacteraemia and most responded to vancomycin. Various coagulation abnormalities including prolongation of P T or P T T , thrombocytopenia or D I C have been reported in patients with septic s h o c k . 11'17'18 In a prospective study of 118 patients with Staphylococcus epidermidis bacteraemia, Martin et al. found D I C in IO patients but no other details were given2 In our study, normal coagulation was found in seven patients with septic shock, none of whom died. When coagulation was abnormal, however, 44 % (7/~6) of patients died. T w o of these patients who had D I C both died. In contrast, there was only one death (5"9 %) among patients without septic shock having coagulopathy. T h e most common feature associated with bacteraemia was the use of indwelling catheters. 18,19-21 T h e reported incidence of bacteraemia due to CNS associated with intravenous catheters has increased dramatically in the last few years. This has been particularly so for central venous catheters such as routine subclavian and Hickman catheters. 2 In one report, CNS were responsible for approximately I8 % of cases of bacteraemia associated with intravascular devices. 2 Forse and co-workers 22 reported an epidemic of nosocomial bacteraemia due to CNS among I3 patients in their surgical intensive care unit between I977 and I978. T h e source of infection was attributed to intravascular catheters in most of these patients. A recent study 3 also showed that I 18 patients had an indwelling intravascular catheter. In 44 (37 %) of them, there was evidence of catheter-related infection including inflammation at the catheter site, phlebitis or a positive semi-quantitative catheter culture. This finding agrees with our study in which an arterial catheter was the most common source of bacteraemia for the majority of patients with and without septic shock. T h e duration of arterial cannulation is often thought to be an important influence in arterial catheter infection. Band and Maki have advocated removal or changing of catheters every 4 day s.23
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Others, however, have not found any association between arterial catheter infection and the catheter being in place for more than 4 day s.24 Duration of arterial catheters being in place did not exceed 4 days in any of our patients. T h e r e are no clear cut recommendations concerning the removal or changing of central venous catheters used for measuring central venous pressure. In our study, 35 patients were treated with vancomycin. T h e use of vancomycin was confirmed by Karchmer and associates 25 who reported that 83 % of S . epidermidis isolates from their patients with prosthetic valve endocarditis were resistant to methicillin. Other investigators have also confirmed that vancomycin is the drug of choice for methicillin-resistant CNS. z In many cases, any foreign body should be removed. 2 In our study, all catheters were removed and new catheters inserted at different sites once bacteraemia was suspected. Several workers ~'4 have reported high mortality in cases of bacteraemia due to CNS, the rate varying between I8"5 % and 34 %.4 This accords with our study in which the overall mortality of bacteraemia was I6'7% (8/48). T h e mortality was much higher, however, in patients with septic shock (30"4 %) than in patients without septic shock (4"0 %, P < 0"05). By contrast, Ponce and WenzeP reported a mortality of 50 % in patients with septic shock. In addition, several authors have reported higher mortality in selected populations such as immunocompromised patients, surgical patients, and untreated patients. 3.26 T h e former is in agreement with our study in which mortality was higher in immunocompromised patients than in nonimmunocompromised. Although necropsies were not performed due to religious reasons, deaths among our patients were probably due to CNS bacteraemia a n d / o r shock since they continued to have clinical and laboratory evidence of infection despite aggressive therapy. T h e evidence included persistently positive blood cultures, continuous fever, leucocytosis and hypotension. In conclusion, septic shock caused by CNS is a major threat to patients in hospital, particularly those in intensive care units. These organisms, when isolated from blood, should not be dismissed as contaminants. Cultures should be repeated and results correlated with the clinical state of the patient. Since the n u m b e r of patients in our series is small, further studies are required to confirm our findings. Adhering to the basic principles of infection control, including the care of indwelling catheters and assessment of risk factors, is important in reducing morbidity and mortality of such infection. (We thank the nursing staff of the ICU at King Khalid University Hospital for their cooperation and Ms Vergie Vicente for secretarial assistance.) References
i. StillmanRI, Wenzel RP, Donowitz LC. Emergenceof coagulase-negadvestaphylococcias major nosocomialblood stream pathogens. Infect Control I987; 8: IO9-112. 2. LowlyFD, Hammer SM. Staphylococcus epidermidis infections.Ann Intern Med I983; 99: 834-839. 3. Martin MA, Pfaller MA, Wenzel RP. Coagulase-negativestaphylococcalbacteraemia-mortality and hospital stay. Ann Intern Med I989; IIO: 9-I6. 4-Ponce de Leon S, Wenzel RP. Hospital-acquired blood stream infections with Staphylococcus epidermidis: review of ioo cases. Am J Med I984; 77: 639-644.
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5. Scherer LR, West KW, Weber TR, Kleiman M, Grosfeld JL. Staphylococcus epidermidis sepsis in pediatric patients: clinical and therapeutic considerations. J Ped Surg 1984; 19: 358-361. 6. Donowitz LG, Haley CE, Gregory WW, Wenzel RP. Neonatal intensive care unit bacteremia: emergence of gram-positive bacteria as major pathogens. Am J Infect Control 1987; 15: 141-147. 7. Niehart RE, Fried JS, Hodge GR. Coagulase-negative staphylococci. South M e d J 1988; 81 : 491-5oo. 8. Wade JC, Schimpff SC, Newman KA, Wiernik PH. Staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-508. 9. McCabe WR, Jackson GG. Gram-negative bacteraemia I. Etiology and ecology. Arch Intern Med 1962; i i o : 845-855. IO. Chowdhury MNH. Blood culture techniques. Saudi Med J 1981 ; 2: 225-228. II. Dahmash NS, Chowdhury MNH, Fayed DF. Septic shock in critically ill patients: aetiology, management and outcome. J Infect 1993; 26: 159-17o. 12. Stokes EJ, Ridway GL. Clinical Bacteriology. 6th ed. London: Edward Arnold, 1987: 204--222. 13. Kreger BE, Craven DE, Carling PC, McCabe WR. Gram-negative bacteremia III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am 37 Med I98o; 86: 344-355. 14. Dahmash NS, Fayed DF, Chowdhury MNH. Bacteraemia in a medical intensive care unit in Saudi Arabia. Med Sci Res 1993 ; 21 : 4o9-412. 15. Cleri DJ, Corrado ML, Seligman SJ. Quantitative culture of intravenous catheters and other intravascular inserts. 37 Infect Dis 198o; 141 : 781-786. 16. Kirchhof LV, Sheagren JN. Epidemiology and clinical significance of blood cultures positive for coagulase-negative staphylococcus. Infect Control 1985 ; 6: 479-486. 17. Poskitt TR, Poskitt PK. Thrombocytopenia of sepsis. The role of circulating IgG containing immune complexes. Arch Intern Med 1985 ; 145: 891-895. 18. Balk RA, Bone RC. The septic syndrome: definition and clinical implications. Crit Care Clin 1989; 5: 1-8. 19. Perkins CM, Dascomb HE. Intravascular device-related infections. Prob Crit Care 199o; 4 : 21-44. 2o. Lowder JN, Lazarus HM, Herzig RH. Bacteraemias and fungemias in oncologic patients with central venous catheters: changing spectrum of infection. Arch Intern Med 1982; 142: 1456-1459 • 2I. Dahmash NS, Fayed DF, Chowdhury MNH. Arterial line-associated infection. Med Sci Res 1993; 21: 2o7-21o. 22. Forse RA, Dixon C, Bernard K, Martinez L, McLean APH, Meakins JL. Staphylococcus epidermidis: an important pathogen. Surgery 1979; 86 : 507-514. 23. Band JD, Maki DG. Infections caused by arterial catheters used for hemodynamic monitoring. Am J Med 1979; 67:735-741. 24 Leroy O, Billian V, Beuscart C, Santre C, Chidiac C, Mouton Y. Nosocomial infections associated with long-term radial artery cannulation. Intensive Care Med 1989; 15 : 241-245. 25. Karchmer AW, Archer GL, Dismukes WE. Staphylococcus epidermidis causing prosthetic valve endocarditis: microbiologic and clinical observations as guide to therapy. Ann Intern Med 1983; 98: 447-455. 26. Burchard KW, Minor LB, Slotman GJ, Gann DS. Staphylococcus epidermidis sepsis in surgical patients. Arch Surg 1984; 119: 96-1oo.
Coagulase-negative staphylococcal bacteraemia with special r e f e r e n c e to s e p t i c s h o c k : e x p e r i e n c e i n a n i n t e n s i v e c a r e u n i t N a b i l S. D a h m a s h , I M o h a m m e d N. H. C h o w d h u r y 2 a n d D e s o u k y F. F a y e d 3
Departments of 1Medicine, 2Microbiology, and aPharmacy, College of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia Accepted for publication IO May I994 Summary During a period of 4"5 years, 48 patients with bacteraemia due to coagulase-negative staphylococci were studied prospectively in order to evaluate their clinical profile, management and outcome. There were 25 males and 23 females with ages ranging between I3 and Ioo years. Over 60 ~/o of patients belonged to the age group 30 to 69 years. Shock was recorded in 23 (48 ~/o) of the 48 patients. Of the shocked patients, i6 were immunocompromised and also had abnormal coagulation. Their mortality was 44 %. By contrast, none of the immunocompromised patients without shock died. Abnormal coagulation was found in I7 patients without septic shock. Their mortality was 5"9 %. The commonest underlying disease was respiratory failure especially in shocked patients. The source of infection was identified in the majority of cases. In addition, most patients had an indwelling intravascular catheter especially an arterial one. The overall mortality was I6"7 % (8/48). It was significantly higher in patients with shock than in those without shock (30"4% vs. 4'0%, P < 0'05).
Introduction Coagulase-negative staphylococci ( C N S ) , previously regarded as harmless commensal, contaminant, or n o n - p a t h o g e n i c organisms, have emerged in recent years as serious pathogens among patients in hospital. 1-4 T h e r e has been a significant increase in the incidence of infection due to C N S and which has been attributed to recent advances in medical technology. T h e y are a major cause o f bacteraemia associated with intravenous catheters such as H i c k m a n catheters, central venous nutrition catheters, and peripheral intravenous catheters. 2'5,6 T h e y are also a significant cause of endocarditis, otitis media, peritonitis following dialysis, infection of prosthetic heart valves, joint prostheses and vascular shunts. 7 In addition, they have b e c o m e increasingly c o m m o n in patients with granulocytopenia and recipients of bone m a r r o w transplants2' 8 T h e s e infections m a y p r o v e fatal and also prolong the duration of patients' stay in hospital. 3 Although several reports a' 4.7 concerning the importance of bacteraemia due to C N S a m o n g patients in hospital have been published, little is k n o w n a b o u t septic shock in critically ill patients in an intensive care unit ( I C U ) 2 '4 T h e main p u r p o s e of this s t u d y was to report prospectively the incidence, coagulation profile, treatment, and mortality of septic shock due to C N S in the I C U at K i n g Khalid U n i v e r s i t y Hospital ( K K U H ) , Riyadh, Saudi Arabia. In Address correspondence to: Prof M. N. H. Chowdhury, P.O. Box 54803, Riyadh 11524, Saudi Arabia.
o163-4453/94/o6o295+o9 $08.0o/0
© I994 The British Society for the Study of Infection
296
N. S. D A H M A S H
ET AL.
addition, a comparison of various factors predicting mortality was made between these patients and those without septic shock. K K U H is a major teaching hospital which provides both primary and tertiary care. T h e I C U consists of six beds with all modern facilities. M a t e r i a l s and m e t h o d s
A total of 48 cases of CNS bacteraemia was investigated prospectively in the I C U at K K U H during a period of 54 months from January 1989 to August I993. A case of bacteraemia due to CNS was defined as a patient from whom any species of CNS was isolated from two or more blood culture bottles collected 48 hours after a patient's admission to the medical wards or I C U when clinical evidence of infection was present. Underlying diseases which preceded bacteraemia and/or septic shock were classified as rapidly fatal, ultimately fatal or non-fatal by means of criteria described earlier.9 In 16 cases, which were excluded from the study, other species of bacteria or fungi were isolated from the same sets of blood cultures. If a patient had more than one episode of bacteraemia due to CNS, only the first episode was used in the analysis. Blood cultures were collected from patients when bacteraemia and/or septic shock were suspected either in the medical wards or in the I C U as described previously by us. l°'n At least two sets of blood cultures were collected from each patient via peripheral venepuncture. Any species of CNS isolated from at least two different blood samples was considered as clinically significant. A single positive blood culture set was considered to indicate contamination. In cases of doubt, blood cultures were repeated in order to exclude any contamination. In addition, urine, sputum, and swabs from local catheter sites were collected simultaneously from these patients. Cultures, including blood cultures, were also repeated during the course of illness especially at any time when a patient's condition deteriorated. CNS were detected by means of negative coagulase and DNAase tests. T h e y were further identified to species level by use of the API system (Balme Les Grothes 3839o, Montalieu Vaarieu, France). Antibiotic susceptibility was determined by means o f disc diffusion and use of the rotating Stoke's technique) 2 Methicillin susceptibility was determined by means of methicillin strips (25#g) obtained from Mast Laboratories (Bootle, Merseyside, U.K.) and use of salt-agar at 37 °C. Both methicillin sensitive and resistant strains were included with each set of sensitivity plates as controls. 12 Septic shock was defined as a decrease in systolic blood pressure to < 9o m m H g or a 7o m m H g decrease in systolic or diastolic pressure in patients with previously stable hypertensive values. '3'~ In addition, there was progressive deterioration of cellular and tissue perfusion leading to severe metabolic derangement and organ failure in patients with septic shock due to overwhelming infection with CNS. Patients were evaluated on admission to the I C U as regards age, sex, primary diagnosis, presence of indwelling catheters, signs and symptoms, underlying disease, preceding infection, pertinent laboratory data and antibiotic sensitivities as well as antibiotics used before and during septic episodes. Fever, leucocytosis and leucopenia were
Staphylococcal bacteraemia
297
defined in accordance with previous publications. 11'1~ A source of infection was identified when isolates from sites of inflammation matched with those from blood cultures. H It was deemed advisable to establish whether these isolates were identical or not. This was done by identifying the organisms by means of the API system (Balme Les Grothes 38390, Montalieu Vaarieu, France) and also by antibiotic susceptibility pattern. In addition, most patients were observed to have inflammation at the localised site of infection. Molecular and phage typing was not done. All catheters, including arterial catheters, central venous pressure monitoring lines, and Swan-Ganz catheters, were removed and cultured quantitatively according to the method of Cleri et al./5 when clinical evidence suggested bacteraemia. Each catheter tip was washed and flushed through with 2 ml sterile broth. T h e broth was then diluted Ioo-fold and a measured amount cultured on blood and MacConky agars. T h e number of colonyforming units (CFU) per catheter was calculated. A growth of > Iooo C F U was regarded as indicating infection while a growth of < Iooo C F U was considered as indeterminate, probably the result of contamination or indicating an early stage of colonisation. None of the arterial catheters remained in place for more than 4 days. After removal of intravascular catheters, patients were monitored closely. Antibiotics were administered empirically to patients who continued to have clinical evidence of bacteraemia such as persistent fever, leucocytosis and hypotension. T r e a t m e n t was modified, if necessary, as soon as results of the susceptibility of CNS isolated were obtained. In addition to antibiotic treatment, patients with shock received fluid in the form of crystalloids or colloids. Vasopressor drugs were added if there was no response to fluid therapy. 11 Swan-Ganz catheters were inserted in four patients with septic shock and who had a transient response to the administration of fluid. 1~ T h e duration of stay of patients with bacteraemia without shock ranged between 5 and 95 days (mean = I9"8 days) and for those with septic shock between 2 and I25 days (mean = 34"4 days). All patients were followed in the I C U until full recovery or death. Statistical analysis
For comparison among groups, the X2 test and Fisher's exact test were used. P < 0"05 was considered to be significant. Results
A total of 48 patients had bacteraemia due to CNS. Most (35/48) of the infections were acquired in the ICU, while 27 % (I3/48) were acquired in the medical wards. Table I shows the clinical and demographic data of 48 patients of whom 48 % (23/48) met the criteria for septic shock. T h e y included Io males and I3 females, their ages ranging from I6 to 8o years (mean = 53"7 years). T h e r e were I5 male and IO female patients without septic shock with ages ranging from I3 to IOO years (mean = 47"5). T h e r e was no significant difference in mortality between the sexes and among the various age groups. Most patients with and without septic shock had fever and leucocytosis. Among patients with
298
N . S. D A H M A S H
ET AL.
T a b l e I Clinical and demographic data of patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Variable Age (years) 13 - 2 9 3o--49 50-69 > 7o Total Sex Male Female U n d e r l y i n g disease NF RF UF Fever > 37"8 °C 36-37"8 °C < 36 °C
L e u c o c y t e c o u n t ( x lO9/1) > II'O 4"o-11 < 4"0 Mechanical ventilation Yes No Steroids/Immune suppression Yes No
No.
Bacteraemia Died (%)
7 6 8 4 25
o I o o I
15 IO
No.
Septic shock Died (%)
2 8 7 6 23
I o 3 3 7
o I
IO 13
3 4
5 6 14
o o i
I 6 16
o 2 5
16 8
o i
13 5
4 I
I
o
5
2
15 6 4
o I O
16 5 2
5 2 O
19 6
o I
2o 3
6 i
15 IO
o
16 7
7 o
(4"0)
(7"1)
I
(I0"O)
(30'4)
(33"3) (31"2 )
(43'8)
N F = n o n - f a t a l , R F = rapidly fatal, U F = u l t i m a t e l y fatal.
T a b l e II Mortality related to underlying disease in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Disease R e s p i r a t o r y failure Cerebrovascular accident Diabetes mellitus H e p a t i c failure R e n a l failure Vasculitis Leukaemia/lymphoma/malignant neoplasia Miscellaneous Total
No.
Bacteraemia Died (%)
No.
Septic shock Died (%)
6 4 3 3 I I 5
I o o o o
iz 4 z I I
O
2
I
o
I
o
2
o
o
o
25
I
23
7
(4"0)
3 2 o o 1
(30'4)
Staphylococcal bacteraemia
z99
Table I I I Results of coagulation tests in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Variable Normal coagulation Abnormal coagulation DIC Others
No.
Bacteraemia Died (%)
8
o
z I5
o I
(6'7)
No.
Septic shock Died (%)
7
o
2 14
z 5
(Ioo) (35'7)
DIC = Disseminated intravascular coagulation. septic shock, no significant difference in mortality was noted between those being mechanically ventilated and those not being mechanically ventilated (3o 0/0 vs. 3o'3 %, P > o'o5). Most patients with septic shock were i m m u n o compromised, due either to disease or because they were receiving i m m u n o suppressive drugs. T h e i r mortality was 4 4 % compared to o % mortality among patients who were not i m m u n o c o m p r o m i s e d . (P < o'o5). By contrast, none of the patients without septic shock and who were either receiving ventilatory support or were i m m u n o c o m p r o m i s e d , died. T h e overall mortality of patients with septic shock was 3o'4 % compared to 4"o % mortality among patients without septic shock (P < o'os). Table II shows the underlying diseases and mortality among the 48 patients. Respiratory failure (37"5~o) was the most c o m m o n underlying clinical condition. Of the 48 patients, 39 were being mechanically ventilated. T h e indication for mechanical ventilation was acute respiratory failure secondary to p u l m o n a r y disease in I8 patients. In the remaining 2I patients, mechanical ventilation was required for various reasons including coma as a result of cerebrovascular accident (eight patients), hepatic failure (four patients), progressive lung infiltrates associated with vasculitis (three patients) and malignant haematologic neoplasia (6 patients). Six of the 39 patients died of septic shock. Table I I I shows the results of coagulation tests in the 48 patients. A m o n g those with septic shock, coagulation was found to be normal in seven patients and abnormal in i6 patients. Prolongation o f p r o t h r o m b i n time (PT) was seen in three patients who survived. Prolongation of P T and partial thromboplastin time ( P T T ) was found in four patients while prolongation of P T and thrombocytopenia were found in another four patients with a mortality of o % and 5o %, respectively. Prolongation of P T , P T T , and thrombocytopenia was recorded in two patients, isolated thrombocytopenia in one patient and disseminated intravascular coagulation (DIC) in two patients with a mortality of ioo 0/0 for each group. In patients without septic shock, coagulation was found to be normal in eight patients and abnormal in z7. T h e latter included eight patients with prolonged P T , two with prolonged P T and P T T , two with prolonged P T and thrombocytopenia, two with prolonged P T , P T T , thrombocytopenia and two with D I C . T h r o m b o c y t o p e n i a alone was found in one patient who died. T h e patients with shock and coagulopathy had a higher
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N . S. D A H M A S H
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T a b l e IV Sources of infection in patients with bacteraemia and septic shock due to coagulase-negative staphylococci (n = 48) Source
No.
Total Died
Bacteraemia No. Died
Septic shock No. Died
Arterial catheter Swan-Ganz catheter Central venous catheter
33 2 6
2 o I
2o 2 3
I o o
I3 o 3
I o I
Femoral venous catheter Total catheter-associated
I 42
I 4
o 25
o I
I 17
I 3
Respiratory tract Other Unknown Total
I 3 9 55*
I o 3 8
o 2 2 29
o o o I
i I 7 26**
i o 3 7
* Seven patients had m o r e than one source of infection. ** T h r e e p a t i e n t s h a d m o r e t h a n o n e s o u r c e o f i n f e c t i o n .
mortality than those with coagulopathy b u t w i t h o u t shock (44 % vs. 6 %; P < 0"05). T a b l e IV shows the sources of infection which were identified in most of the patients. Arterial catheters were f o u n d to be the c o m m o n e s t source of infection. F o u r patients had a n o r m a l mental state at the time of septic shock, I6 patients were unresponsive and three sedated, with mortality of 25 %, 37"5 % and o %, respectively. A m o n g patients w i t h o u t septic shock, I I had a n o r m a l mental state while seven were sedated and seven were unresponsive. M o r t a l i t y a m o n g the last group was 20 %. Cultures obtained from blood, catheter sites and catheter tips a r o u n d the time of each patient's deterioration were positive for C N S . E x a m i n a t i o n of other specimens, however, did not reveal any pathogen at that time. O n l y six isolates of C N S were sensitive to methicillin. T h e y included five isolates from patients w i t h o u t septic shock and one f r o m patients with septic shock. All isolates were sensitive to vancomycin. Catheters were r e m o v e d from all patients. Only in seven patients did bacteraemia remit following this procedure. A m o n g the remaining patients, six were treated with cloxacillin and 35 with vancomycin. Discussion
A l t h o u g h bacteraemia caused by C N S is not u n c o m m o n , septic shock due to C N S has rarely been reported. 3'~' 11 T h i s is probably the first comprehensive report o f septic shock due to C N S . Ponce and Wenzel 4 in a study of IO8 episodes of bacteraemia due to C N S in IOO patients over a 7-year period at the University of Virginia Medical Center, n o t e d septic shock in 22 % of their patients. Similarly, M a r t i n et al) f o u n d evidence o f septic shock in I 7 % ( 2 o / I I 8 ) of their patients with bacteraemia due to C N S . T h e y also reported an incidence of I7"5 % for h y p o t e n s i o n in their patients with a single positive blood culture compared to I7 % in patients with two or more positive blood cultures. A striking finding
Staphylococcal bacteraemia
30I
of the present survey was the high incidence of shock (48 %) in our patients. This high incidence is probably due to the fact that these patients were seriously ill requiring admission to the I C U and intensive management. Until recently, shock was rarely mentioned in reviews of bacteraemia caused by organisms other than Gram-negative bacilli. All of our patients were over the age of 13 years and most of the infections were acquired in the ICU. By contrast, in other studies, 3'4 a significant n u m b e r of patients were premature infants or patients in paediatric or surgical intensive care units. T h e isolation of CNS from blood often presents the clinical microbiologist with the difficult task of deciding if this reflects true bacteraemia or contamination from the skin. Kirchhoff and Sheagren 16 considered CNS to be true blood pathogens in patients with intravascular devices for whom (I) a high proportion of blood cultures were positive for this organism over a short period of time, (2) cultures became positive in less than 48 hours with a high percentage of both bottles being positive. Recently, Martin et al. 3 found that 40 patients with bacteraemia due to CNS had a single positive blood culture whereas 78 had two or more positive blood cultures. In our series, all patients had genuine CNS bacteraemia since it was confirmed by isolation of the organism from different, multiple sets of blood samples. Most of our cultures were also positive within 48 hours. In addition, patients presented with the clinical features of bacteraemia and most responded to vancomycin. Various coagulation abnormalities including prolongation of P T or P T T , thrombocytopenia or D I C have been reported in patients with septic s h o c k . 11'17'18 In a prospective study of 118 patients with Staphylococcus epidermidis bacteraemia, Martin et al. found D I C in IO patients but no other details were given2 In our study, normal coagulation was found in seven patients with septic shock, none of whom died. When coagulation was abnormal, however, 44 % (7/~6) of patients died. T w o of these patients who had D I C both died. In contrast, there was only one death (5"9 %) among patients without septic shock having coagulopathy. T h e most common feature associated with bacteraemia was the use of indwelling catheters. 18,19-21 T h e reported incidence of bacteraemia due to CNS associated with intravenous catheters has increased dramatically in the last few years. This has been particularly so for central venous catheters such as routine subclavian and Hickman catheters. 2 In one report, CNS were responsible for approximately I8 % of cases of bacteraemia associated with intravascular devices. 2 Forse and co-workers 22 reported an epidemic of nosocomial bacteraemia due to CNS among I3 patients in their surgical intensive care unit between I977 and I978. T h e source of infection was attributed to intravascular catheters in most of these patients. A recent study 3 also showed that I 18 patients had an indwelling intravascular catheter. In 44 (37 %) of them, there was evidence of catheter-related infection including inflammation at the catheter site, phlebitis or a positive semi-quantitative catheter culture. This finding agrees with our study in which an arterial catheter was the most common source of bacteraemia for the majority of patients with and without septic shock. T h e duration of arterial cannulation is often thought to be an important influence in arterial catheter infection. Band and Maki have advocated removal or changing of catheters every 4 day s.23
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N. S. D A H M A S H E T A L .
Others, however, have not found any association between arterial catheter infection and the catheter being in place for more than 4 day s.24 Duration of arterial catheters being in place did not exceed 4 days in any of our patients. T h e r e are no clear cut recommendations concerning the removal or changing of central venous catheters used for measuring central venous pressure. In our study, 35 patients were treated with vancomycin. T h e use of vancomycin was confirmed by Karchmer and associates 25 who reported that 83 % of S . epidermidis isolates from their patients with prosthetic valve endocarditis were resistant to methicillin. Other investigators have also confirmed that vancomycin is the drug of choice for methicillin-resistant CNS. z In many cases, any foreign body should be removed. 2 In our study, all catheters were removed and new catheters inserted at different sites once bacteraemia was suspected. Several workers ~'4 have reported high mortality in cases of bacteraemia due to CNS, the rate varying between I8"5 % and 34 %.4 This accords with our study in which the overall mortality of bacteraemia was I6'7% (8/48). T h e mortality was much higher, however, in patients with septic shock (30"4 %) than in patients without septic shock (4"0 %, P < 0"05). By contrast, Ponce and WenzeP reported a mortality of 50 % in patients with septic shock. In addition, several authors have reported higher mortality in selected populations such as immunocompromised patients, surgical patients, and untreated patients. 3.26 T h e former is in agreement with our study in which mortality was higher in immunocompromised patients than in nonimmunocompromised. Although necropsies were not performed due to religious reasons, deaths among our patients were probably due to CNS bacteraemia a n d / o r shock since they continued to have clinical and laboratory evidence of infection despite aggressive therapy. T h e evidence included persistently positive blood cultures, continuous fever, leucocytosis and hypotension. In conclusion, septic shock caused by CNS is a major threat to patients in hospital, particularly those in intensive care units. These organisms, when isolated from blood, should not be dismissed as contaminants. Cultures should be repeated and results correlated with the clinical state of the patient. Since the n u m b e r of patients in our series is small, further studies are required to confirm our findings. Adhering to the basic principles of infection control, including the care of indwelling catheters and assessment of risk factors, is important in reducing morbidity and mortality of such infection. (We thank the nursing staff of the ICU at King Khalid University Hospital for their cooperation and Ms Vergie Vicente for secretarial assistance.) References
i. StillmanRI, Wenzel RP, Donowitz LC. Emergenceof coagulase-negadvestaphylococcias major nosocomialblood stream pathogens. Infect Control I987; 8: IO9-112. 2. LowlyFD, Hammer SM. Staphylococcus epidermidis infections.Ann Intern Med I983; 99: 834-839. 3. Martin MA, Pfaller MA, Wenzel RP. Coagulase-negativestaphylococcalbacteraemia-mortality and hospital stay. Ann Intern Med I989; IIO: 9-I6. 4-Ponce de Leon S, Wenzel RP. Hospital-acquired blood stream infections with Staphylococcus epidermidis: review of ioo cases. Am J Med I984; 77: 639-644.
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5. Scherer LR, West KW, Weber TR, Kleiman M, Grosfeld JL. Staphylococcus epidermidis sepsis in pediatric patients: clinical and therapeutic considerations. J Ped Surg 1984; 19: 358-361. 6. Donowitz LG, Haley CE, Gregory WW, Wenzel RP. Neonatal intensive care unit bacteremia: emergence of gram-positive bacteria as major pathogens. Am J Infect Control 1987; 15: 141-147. 7. Niehart RE, Fried JS, Hodge GR. Coagulase-negative staphylococci. South M e d J 1988; 81 : 491-5oo. 8. Wade JC, Schimpff SC, Newman KA, Wiernik PH. Staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982; 97: 503-508. 9. McCabe WR, Jackson GG. Gram-negative bacteraemia I. Etiology and ecology. Arch Intern Med 1962; i i o : 845-855. IO. Chowdhury MNH. Blood culture techniques. Saudi Med J 1981 ; 2: 225-228. II. Dahmash NS, Chowdhury MNH, Fayed DF. Septic shock in critically ill patients: aetiology, management and outcome. J Infect 1993; 26: 159-17o. 12. Stokes EJ, Ridway GL. Clinical Bacteriology. 6th ed. London: Edward Arnold, 1987: 204--222. 13. Kreger BE, Craven DE, Carling PC, McCabe WR. Gram-negative bacteremia III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am 37 Med I98o; 86: 344-355. 14. Dahmash NS, Fayed DF, Chowdhury MNH. Bacteraemia in a medical intensive care unit in Saudi Arabia. Med Sci Res 1993 ; 21 : 4o9-412. 15. Cleri DJ, Corrado ML, Seligman SJ. Quantitative culture of intravenous catheters and other intravascular inserts. 37 Infect Dis 198o; 141 : 781-786. 16. Kirchhof LV, Sheagren JN. Epidemiology and clinical significance of blood cultures positive for coagulase-negative staphylococcus. Infect Control 1985 ; 6: 479-486. 17. Poskitt TR, Poskitt PK. Thrombocytopenia of sepsis. The role of circulating IgG containing immune complexes. Arch Intern Med 1985 ; 145: 891-895. 18. Balk RA, Bone RC. The septic syndrome: definition and clinical implications. Crit Care Clin 1989; 5: 1-8. 19. Perkins CM, Dascomb HE. Intravascular device-related infections. Prob Crit Care 199o; 4 : 21-44. 2o. Lowder JN, Lazarus HM, Herzig RH. Bacteraemias and fungemias in oncologic patients with central venous catheters: changing spectrum of infection. Arch Intern Med 1982; 142: 1456-1459 • 2I. Dahmash NS, Fayed DF, Chowdhury MNH. Arterial line-associated infection. Med Sci Res 1993; 21: 2o7-21o. 22. Forse RA, Dixon C, Bernard K, Martinez L, McLean APH, Meakins JL. Staphylococcus epidermidis: an important pathogen. Surgery 1979; 86 : 507-514. 23. Band JD, Maki DG. Infections caused by arterial catheters used for hemodynamic monitoring. Am J Med 1979; 67:735-741. 24 Leroy O, Billian V, Beuscart C, Santre C, Chidiac C, Mouton Y. Nosocomial infections associated with long-term radial artery cannulation. Intensive Care Med 1989; 15 : 241-245. 25. Karchmer AW, Archer GL, Dismukes WE. Staphylococcus epidermidis causing prosthetic valve endocarditis: microbiologic and clinical observations as guide to therapy. Ann Intern Med 1983; 98: 447-455. 26. Burchard KW, Minor LB, Slotman GJ, Gann DS. Staphylococcus epidermidis sepsis in surgical patients. Arch Surg 1984; 119: 96-1oo.