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A new approach to the management of Broviac catheter infection
Journal of Hospital Infection (1992) 22, 109-l 16
A new approach
to the management catheter infection
J. S. Rao, A. O’Meara *, T. Harvey
of Broviac
and F. Breatnach
Departments of Oncology and Microbiology, Our Lady’s Hospital Children, Crumlin, Dublin 12, Ireland Accepted for publication
for Sick
14 July 1992
Summary:
Infection continues to be a major complication of the use of indwelling venous catheters. In an attempt to avoid removal of the catheter and to minimize the systemic side-effects of antibiotics, the potential value of in-situ treatment of confirmed Broviac catheter infection was assessed in carefully selected patients attending an oncology unit. Fourteen episodes from 11 children were included in the study. A variety of organisms were encountered. Infective episodes were divided into two categories: (a) those occurring in patients with negative peripheral blood cultures and neutrophil count greater than 1.5 X lo9 1-i which were treated only by local instillation of heparinized antibiotic &hourly for 7-14 days (N=S); (b) those occurring simultaneously with positive peripheral blood culture (or peripheral blood culture not performed) regardless of neutrophil count, or infection restricted to Broviac catheter but with a neutrophil count of less than 1.5 x lo9 1-i; these were treated, with one exception, as above with the addition of systemic antibiotics (N= 6). Treatment was successful in 100% of infective episodes with negative cultures achieved between 5 and 12 days. Catheters remained in use a mean of 118 days following treatment of infection. This approach has obvious advantages but requires careful patient selection and monitoring. It prolongs the catheter life, obviates the need for systemic antibiotics for a local infection, and with appropriate instruction to parents and family practitioner, treatment may be administered on an outpatient basis. Keywords:
Broviac
catheter
infection;
intracatheter
antibiotic.
Introduction Indwelling catheters are intended for long term vascular access and are of particular value in the care of paediatric oncology patients. Sepsis, however, is the most common serious complication of continued catheter use3.1m3 Recommended management of infection varies from removal of the catheter to systemic administration of appropriate antibiotics through the catheter or peripheral vein.re4 Catheter-related infections have previously been divided into four main categories: exit site infection, tunnel infection, septic thrombophlebitis and septicaemia. Infection, however, may also occur within the lumen of the Correspondence 019S-6701/92/100109+08
to: Dr Anne O’Meara. SOS.OO/O
0 1992 The Hospital
109
Infection
Society
110
J. S. Rao et al.
catheter either in isolation or together with any of the above described infections. Patients with intra-catheter infection may develop fever, chills and rigors, within 1-2 h of flushing the catheter. This procedure presumably results in bacteraemia which, in the presence of an adequate neutrophil count, usually resolves without major consequence. The focus of infection, however, still remains within the catheter, where host defences have little access. In an attempt to avoid removal of the Broviac catheter and to minimize the side effects of systemic antibiotics, a policy was adopted of in-situ treatment of suspected and later confirmed intra-Broviac catheter infection. This approach differed from most other studies in that the catheter, rather than the patient, was treated with antibiotics in selected cases.
Patients
and methods
attending the oncology Fourteen episodes occurring in 11 patients department of Our Lady’s Hospital for Sick Children, Dublin, Ireland over a 12-month period were included prospectively in the study. The ages ranged from 1 year 8 months to 13 years 3 months with a median of 6 years. There were eight males and three females. Informed consent was obtained in all cases. Fungal infection was not included. Intra-catheter infection was clinically defined as a documented increase in temperature (> 38*5”C), associated with chills or rigors which settled spontaneously or with anti-pyretic measures, in an otherwise well child, following flushing of the Broviac catheter; subsequent culture of Broviac fluid was undertaken to confirm infection (i’V= 13). The study was later extended to include a positive bacterial growth from Broviac catheter fluid in one asymptomatic child undergoing random routine culture prior to chemotherapy as part of the surveillance policy of the unit. Patients were then divided into two groups according to the criteria listed in Table I, and reviewed regularly throughout the study period. All patients had a single lumen 6.6 FR Broviac catheter (cat. no. 60010), 90 cm in length with a lumen size of 1 mm and an approximate priming volume of O-7 ml. A rubber bung (lN-Stopfen, Braun) was attached to the exit site of the catheter, the approximate priming volume of which was 0.2 ml. Swabs from catheter exit sites were plated on to blood and MacConkey agar and cultured aerobically for 48 h. Broviac catheter contents were inoculated into each of two blood culture bottles (Bactec 7D and 6B) which were cultured aerobically and anaerobically respectively at 37°C for 5 days. The aerobic cultures were agitated for the first 24 h of incubation. The first 1 ml containing a heparinized saline solution, ‘Hepsal’ (Fisons), was cultured separately; this was identified as Broviac catheter fluid. The subsequent 1 ml of blood, labelled Broviac catheter blood, was also cultured separately. Peripheral venous cultures were also performed in all but two
Antibiotics
I. Dejhition
TABLE
Group (a)
and Broviac
catheter
of patient
study groups Group
1 (N=8)
Clinical evidence of catheter infection; infection confirmed culture of Broviac fluid
(b)
Negativfe
peripheral
(c)
+ Circulating neutrophil than 1.5 X lo9 1-l
blood
2 (N=6)
(a)
As group
la
(b)
PositivTperipheral not done)
(c)
Intraca%eter infection with negative peripheral blood culture but neutrophil count less than 1.5 X lo9 1-l
on
culture
count
111
infection
more
blood
culture
(or
patients (who refused venepuncture at that particular time, see Table I, Group 2b). As systemic infection could therefore not be excluded in these patients, they were treated also with systemic antibiotics (see Table II). At 8-hourly intervals, 1 ml of Broviac catheter fluid (for convenience this volume was used) was withdrawn and discarded and 40 mg amikacin in 0.8 ml (amikacin sulphate paediatric injection 100 mg 2 ml-‘, Bristol Myers) was injected with 0.1 ml of preservative-free heparin (Leo Laboratories, 1000 iuml-‘) into the catheter. Full blood count was performed daily. Amikacin levels from peripheral blood were done on day 3, using a polarized fluorescence immunoassay (Abbott). Patients in Group 2 were also treated with piperacillin and amikacin systemically, administered through a peripheral vein, in accordance with the policy of the unit for management of infection in neutropenic patients, unless otherwise stated (see Table II). Antibiotic levels in serum were maintained within the therapeutic range in all patients in Group 2. Cultures were repeated on days 3, 7, 10 and 14 after omission of a single dose of amikacin and substitution with ‘Hepsal’, which was allowed to dwell within the catheter for 8 h prior to culture. Treatment was continued until cultures were reported as sterile. Cultures were again checked (a) immediately prior to discontinuing antibiotic, (b) 1 week after completion of treatment, and surveillance cultures were also performed at different time intervals within 6 weeks of completion of antibiotic therapy. The catheter tip was cultured on removal in all instances: tips were rolled on the surface of a chocolate agar plate (7% heated horse blood in Oxoid Columbia agar base cm 331) and incubated in 10% CO, at 37°C. The outside of the tips were then wiped with a sterile alcohol impregnated swab and placed in cooked meat broth (Mast 120) and incubated at 37°C for 24 h. Subcultures were incubated in 10% CO,. Results
A total of 16 organisms were cultured over the study period: nine were Gram-negative bacilli, five were Gram-positive cocci, one a Gram-negative
2
1
fluid
faecalis
pneumoniae
Staphylococcus epidermidis (3 isolates) Staphylococcus epidermidis Staphylococcus epidermidis
Enterococcus faecalis Serratia liquefaciens Enterobacter cloacae Aeromonas sp. Staphylococcus aureus
Klebsiella
Corynebacterium sp. Veillonella sp . Klebsiella pneumoniae Klebsiella pneumoniae Viridans streptococcus Acinetobacter sp. Klebsiella pneumoniae Escherichia coli Citrobacter freundii Enterococcus faecalis Citrobacter freundii Enterobacter sp.
Enterococcus
Broviac blood
according
sp
ND
(1 isolate) S. epidermidis
(1 isolate) S. epidermidis S. epidermidis
S. epidermidis
S. aureus
Bacillus
amikacin( 3); erythromycin(4) amikacin
amikacin
amikacin
amikacin(4); ampicillin( 10)
amikacin
-
ND
amikacin
-
12)
Antibiotics
amikacin(2)*; ampicillin(7) amikacin
Local
infections
amikacin amikacin(2); cefotaxime( amikacin amikacin amikacin
-
-
blood
catheter
S. epidermidis
E. faecalis S. liquefaciens Ent. cloacae Aeromonas sp. S. aureus
K. pneumoniae
site
of Broviac
Peripheral
to culture
K. pneumoniae K. pneumoniae Viridans streptococcus Acinetobacter sp. K. pneumoniae E. coli C. freundii E. faecalis C. freundii Enterobacter sp.
Broviac
findings
- = No organism isolated, ND = not done. * ( ) Duration of antibiotic (days). t - =No therapy given.
11
7
6
4 Cc)
3 (a)
Group 2
10
i 9
4 (a) 4 (b)
3 (b)
Group 1
Patient No.
Culture
TABLE I I. Details
+
piperacillin amikacin piperacillin amikacin
+
+
piperacillin + amikacin + flucloxacillin -
ampicillin
piperacillin amikacin
-t
Systemic
10
7
7
10
14
7
7
7” 10
14 14
9 14
Duration of treatment (days)
F;
Antibiotics
and Broviac
catheter
infection
113
coccus and one a Gram-positive bacillus (Table II). In eight of 14 episodes one species was grown, two species grew in each of two episodes, two had three species while in one episode four different organisms were grown. All Broviac infections were treated empirically with amikacin until sensitivities were reported at 48 h. Three species isolated from different episodes of infection (Enterococcus fuecalis, a viridans streptococcus and Staphylococcus epidermidis) (patients 1, 4b, 3a and 7, Table II) were resistant to amikacin and subsequent choice of antibiotic was dictated by antibiotic sensitivity pattern (Table II). Nine infective episodes were treated with intra-catheter antibiotic only, i.e. all patients in Group 1 and patient 6 in Group 2. In the latter patient, Staphylococcus epidermidis was cultured from an initial peripheral blood sample only; the patient was clinically well at the time and not neutropenic. It was considered appropriate to defer systemic treatment and Broviac catheter cultures were sterile 5 days after local treatment. Amikacin levels in peripheral blood were performed in three patients in Group 1 and none was detected. All remaining infections were additionally treated with systemic antibiotics. In the infective episode (a) of patient 3 a Bucillus sp. was recovered from peripheral blood, which had not been recovered from Broviac fluid or blood cultures. This patient was not neutropenic and was also clinically well; the organism was sensitive to ampicillin which was subsequently given as systemic treatment. The average time taken to obtain the first negative culture was 8 days (range 5-12 days). Treatment was continued 48 h after cultures became negative in all cases. All cultures were sterile 1 week after completion of antibiotic therapy and follow-up cultures over a 6-week period remained negative. Three patients developed a further Broviac infection (patients nos. 3, 4 and 6); the interval between first and second infection in patient 3 was 10 weeks, intervals to second and third infections in patient 4 were both 13 weeks. Klebsiellu pneumoniue was one of two organisms isolated in Broviac catheter fluid in the second episode in patient no. 4; although typing was not performed, the antibiotic sensitivity pattern was similar to that of the isolate obtained in the initial infection. As both isolates were sensitive to cefotaxime, intra-Broviac treatment with amikacin was discontinued after 48 h. Seven weeks after initial infection, patient no. 6 grew S. epidermidis in Broviac fluid, sensitive only to vancomycin. This was not treated further as therapy had been completed and a decision to remove the catheter was made. The tip of the catheter, not surprisingly, also grew S. epidermidis (see Table III). S. epidermidis was isolated from the tips of two other Broviac catheters on removal; both patients had previously had S. epidermidis catheter infections which, in each case, was treated with intra-Broviac amikacin. Through a laboratory oversight, sensitivity of S. epidermidis to amikacin was not tested
J. S. Rao et al.
114 TABLE III. Patient
No.
Group
1
Reason for removal Broviac catheter
Completion of Completion of Not removed Not removed Completion of Completion of Died; Broviac Died; Broviac
69; 95 150 159
2 1:
7 11
Duration of catheter life following antibiotic treatment (days) 122 127 99
: (b) 4 (4 (b)
Group 2 3 (4 ; (cl
Follow-up of Broviac catheter usefollowing antibiotic therapy of
Catheter tip culture on removal
treatment treatment
Sterile Sterile
treatment treatment in situ
Sterile Sterile
in situ
2 114 70 120
Completion Not removed Completion Completion Completion Completion
2:; 140
of treatment of of of of
treatment treatment treatment treatment
Sterile Sterile
S. epidermidi? S. epidermidis S. epidermidis
- = Not performed. *=See Results, fourth paragraph.
in one patient (no. 7); the organism was, however, resistant to gentamicin but sensitive to erythromycin and piperacillin. Intra-Broviac treatment was changed to 40 mg erythromycin (erythromycin lactobionate 1 g 20 ml-‘, Abbott) until eradication of infection, and systemic treatment with piperacillin and amikacin was continued for 7 days. Staphylococcus epidermidis in patient no. 11 was sensitive to amikacin and this patient was also treated with systemic amikacin and piperacillin. Broviac exit sites remained clinically uninfected in all patients throughout the study period. A positive exit site culture was, however, obtained in three patients at the time of Broviac catheter infection: patients 1 and 6 grew S. epidermidis and patient 5 Acinetobacter sp. All three patients were treated with intra-Broviac antibiotic only and the exit sites were cleaned with 0.5 % w/v chlorhexidine gluconate (‘Hibidil’, ICI Pharmaceuticals). Follow-up cultures after completion of treatment were negative in all patients. The catheters remained in use from 51 to 249 days (mean 118 days) following successful treatment of intra-Broviac infection (Table III). All catheters remained in situ until completion of treatment or until death from progression of the underlying disease. Discussion
There is no consensus on the nor the management catheters,’
approach to maintenance of Broviac of Broviac catheter infection.2-4 As
Antibiotics
and Broviac
catheter
infection
115
intracatheter infection is the predominant infectious complication experienced in this unit, the study was restricted to these patients. Schwartz et al., 6 in an innovative approach to prevention of intra-Broviac infection, showed that incorporation of vancomycin into heparin flushes reduced the incidence of infection with vancomycin sensitive organisms compared with a control group. Flynn et al., 4 in a study of treatment of catheter related infection by in-situ administration of antibiotics, i.e. systemic antibiotics through the infected line, concluded that ‘further improvement in management of patients with catheter related bacteraemia might be achieved by lengthening the time that antibiotic solutions dwell within the catheter.’ It would therefore appear that this study is a natural progression from that of Flynn et al., who were successful in eradicating Broviac related infection in 65% of patients. As Gram-positive cocci have, in previous series, been the predominant organisms associated with Broviac catheter infection2 the choice of amikacin for treatment merits clarification: vancomycin was initially explored as the antibiotic of choice but had to be abandoned because of incompatibility, at least in the authors’ hands, with heparinized saline solution. This is in contrast to the experience of Schwartz et aL6 who experienced no such incompatibility owing, most likely, to considerably lower doses of vancomycin (25 ltg ml-‘) and heparin (1 unit hep ml-‘). The broad antibacterial spectrum of activity of amikacin, on the other hand, which includes Gram-positive cocci, has made it the agent of choice in many life-threatening infections. By exposure of organisms to amikacin over a prolonged period of time at a concentration many times the minimum inhibitory concentration, activity against less sensitive organisms might be enhanced. The predominance of Gram-negative infections in this study may also be a major factor responsible for success in eradicating most infective episodes. Two infections were due to streptococci, and both isolates were resistant to amikacin which, given its limited activity against this group of organisms, is not surprising. Three infections caused by S. epidermidis, also grew S. epidermidis from the catheter tip on removal. While one of these infections had not been treated prior to catheter removal (patient no. 6, Table III), intervals of 249 and 140 days respectively elapsed from eradication of infection to removal of catheter in the other two patients, and random cultures in the interim had also been sterile. In the light of our experience, we would recommend that (a) amikacin be the antibiotic of first choice when intra-Broviac treatment only is considered, (b) if Gram-positive organisms are isolated, therapy may be changed as antibiotic sensitivity tests dictate and (c) where S. epidermidis is isolated, the incorporation of streptokinase into the catheter flush might remove the infected microthrombi which may be associated with S. epidermidis infections because of the production of polysaccharide slime by the organism. Quantitative cultures have recently been reported as useful in diagnosing
J. S. Rao et al.
116
catheter-related infection7 but these have been found to be of little value in the management of Broviac catheter-related sepsis.2 While they were not performed in this study, the rigid adherence to differential Broviac culture enabled a diagnosis to be made with confidence. Antibiotic was discontinued when 48-h cultures were reported sterile; follow-up cultures 1 week and 6 weeks after discontinuing antibiotic therapy were negative in all instances. This data would appear to indicate that the need for up to 2 weeks further antibiotic therapy following clearance of Broviac infections, as others have advocated,2 may well be unnecessary with the possible exception of S. epidermidis infection. While it is obvious to some, it nevertheless is important to emphasize that this approach to treatment of Broviac catheter infection should be restricted to carefully selected non-neutropenic patients. Where intravenous antibiotics were given, administration was through a peripheral vein in all instances so that bias could not be introduced. The authors would now recommend that for patients requiring systemic antibiotics, such as those categorized as Group 2 in this study, administration through the Broviac catheter is appropriate, followed by local instillation of antibiotic as stated. In conclusion, eradication of intra-Broviac infection is achievable by in-situ local treatment in carefully selected patients. Amikacin would appear to be an appropriate first-line antibiotic, but an alternative may be necessary in Gram-positive infections. Treatment can be administered on an outpatient basis. Catheter life is prolonged and inconvenience to family and hospital personnel is minimized. Financial savings are also an added benefit. We would like to thank Dr R. Hone, Clinical Microbiologist, Mater Hospital, Dublin, reviewing the paper, the nursing staff of our oncology ward for their co-operation vigilance and 0. Reddy for secretarial assistance.
for and
References 1. Reilly 2. 3. 4.
2: 7.
JJ, Steed DL, Ritter PS. Indwelling venous access catheters in patients with acute leukemias. Cancer 1984; 53: 219-223. Decker MD, Edwards KM. Central venous catheter infections. Ped Clin N Am 1988; 35: 579-605. Dickinson GM, Bisno AL. Infections associated with indwelling devices: infections related to extravascular devices. Antimicrob Agents Chemother 1989; 33: 602-607. Flynn PM, Shenep JL, Stokes DC, Barrett FF. In-situ management of confirmed central venous catheter related bacteremia. Pediatr Infect Dis J 1987; 6: 729-734. Clarke J, Cox E. Heparinisation of Hickman catheters. Nursing Times 1988; 84: 52-53. Schwartz C, Henrickson KJ, Roghmann K, Powell K. Prevention of bacteremia attributed to luminal colonisation of tunneled central venous catheters with vancomycin-susceptible organisms. J Clin Oncol 1990; 8: 1591-1597. Raucher HS, Hyatt AC, Barzilai A et al. Quantitative blood cultures in the evaluation of septicemia in children with Broviac catheter, J Ped 1984; 104: 29-33.
A new approach
to the management catheter infection
J. S. Rao, A. O’Meara *, T. Harvey
of Broviac
and F. Breatnach
Departments of Oncology and Microbiology, Our Lady’s Hospital Children, Crumlin, Dublin 12, Ireland Accepted for publication
for Sick
14 July 1992
Summary:
Infection continues to be a major complication of the use of indwelling venous catheters. In an attempt to avoid removal of the catheter and to minimize the systemic side-effects of antibiotics, the potential value of in-situ treatment of confirmed Broviac catheter infection was assessed in carefully selected patients attending an oncology unit. Fourteen episodes from 11 children were included in the study. A variety of organisms were encountered. Infective episodes were divided into two categories: (a) those occurring in patients with negative peripheral blood cultures and neutrophil count greater than 1.5 X lo9 1-i which were treated only by local instillation of heparinized antibiotic &hourly for 7-14 days (N=S); (b) those occurring simultaneously with positive peripheral blood culture (or peripheral blood culture not performed) regardless of neutrophil count, or infection restricted to Broviac catheter but with a neutrophil count of less than 1.5 x lo9 1-i; these were treated, with one exception, as above with the addition of systemic antibiotics (N= 6). Treatment was successful in 100% of infective episodes with negative cultures achieved between 5 and 12 days. Catheters remained in use a mean of 118 days following treatment of infection. This approach has obvious advantages but requires careful patient selection and monitoring. It prolongs the catheter life, obviates the need for systemic antibiotics for a local infection, and with appropriate instruction to parents and family practitioner, treatment may be administered on an outpatient basis. Keywords:
Broviac
catheter
infection;
intracatheter
antibiotic.
Introduction Indwelling catheters are intended for long term vascular access and are of particular value in the care of paediatric oncology patients. Sepsis, however, is the most common serious complication of continued catheter use3.1m3 Recommended management of infection varies from removal of the catheter to systemic administration of appropriate antibiotics through the catheter or peripheral vein.re4 Catheter-related infections have previously been divided into four main categories: exit site infection, tunnel infection, septic thrombophlebitis and septicaemia. Infection, however, may also occur within the lumen of the Correspondence 019S-6701/92/100109+08
to: Dr Anne O’Meara. SOS.OO/O
0 1992 The Hospital
109
Infection
Society
110
J. S. Rao et al.
catheter either in isolation or together with any of the above described infections. Patients with intra-catheter infection may develop fever, chills and rigors, within 1-2 h of flushing the catheter. This procedure presumably results in bacteraemia which, in the presence of an adequate neutrophil count, usually resolves without major consequence. The focus of infection, however, still remains within the catheter, where host defences have little access. In an attempt to avoid removal of the Broviac catheter and to minimize the side effects of systemic antibiotics, a policy was adopted of in-situ treatment of suspected and later confirmed intra-Broviac catheter infection. This approach differed from most other studies in that the catheter, rather than the patient, was treated with antibiotics in selected cases.
Patients
and methods
attending the oncology Fourteen episodes occurring in 11 patients department of Our Lady’s Hospital for Sick Children, Dublin, Ireland over a 12-month period were included prospectively in the study. The ages ranged from 1 year 8 months to 13 years 3 months with a median of 6 years. There were eight males and three females. Informed consent was obtained in all cases. Fungal infection was not included. Intra-catheter infection was clinically defined as a documented increase in temperature (> 38*5”C), associated with chills or rigors which settled spontaneously or with anti-pyretic measures, in an otherwise well child, following flushing of the Broviac catheter; subsequent culture of Broviac fluid was undertaken to confirm infection (i’V= 13). The study was later extended to include a positive bacterial growth from Broviac catheter fluid in one asymptomatic child undergoing random routine culture prior to chemotherapy as part of the surveillance policy of the unit. Patients were then divided into two groups according to the criteria listed in Table I, and reviewed regularly throughout the study period. All patients had a single lumen 6.6 FR Broviac catheter (cat. no. 60010), 90 cm in length with a lumen size of 1 mm and an approximate priming volume of O-7 ml. A rubber bung (lN-Stopfen, Braun) was attached to the exit site of the catheter, the approximate priming volume of which was 0.2 ml. Swabs from catheter exit sites were plated on to blood and MacConkey agar and cultured aerobically for 48 h. Broviac catheter contents were inoculated into each of two blood culture bottles (Bactec 7D and 6B) which were cultured aerobically and anaerobically respectively at 37°C for 5 days. The aerobic cultures were agitated for the first 24 h of incubation. The first 1 ml containing a heparinized saline solution, ‘Hepsal’ (Fisons), was cultured separately; this was identified as Broviac catheter fluid. The subsequent 1 ml of blood, labelled Broviac catheter blood, was also cultured separately. Peripheral venous cultures were also performed in all but two
Antibiotics
I. Dejhition
TABLE
Group (a)
and Broviac
catheter
of patient
study groups Group
1 (N=8)
Clinical evidence of catheter infection; infection confirmed culture of Broviac fluid
(b)
Negativfe
peripheral
(c)
+ Circulating neutrophil than 1.5 X lo9 1-l
blood
2 (N=6)
(a)
As group
la
(b)
PositivTperipheral not done)
(c)
Intraca%eter infection with negative peripheral blood culture but neutrophil count less than 1.5 X lo9 1-l
on
culture
count
111
infection
more
blood
culture
(or
patients (who refused venepuncture at that particular time, see Table I, Group 2b). As systemic infection could therefore not be excluded in these patients, they were treated also with systemic antibiotics (see Table II). At 8-hourly intervals, 1 ml of Broviac catheter fluid (for convenience this volume was used) was withdrawn and discarded and 40 mg amikacin in 0.8 ml (amikacin sulphate paediatric injection 100 mg 2 ml-‘, Bristol Myers) was injected with 0.1 ml of preservative-free heparin (Leo Laboratories, 1000 iuml-‘) into the catheter. Full blood count was performed daily. Amikacin levels from peripheral blood were done on day 3, using a polarized fluorescence immunoassay (Abbott). Patients in Group 2 were also treated with piperacillin and amikacin systemically, administered through a peripheral vein, in accordance with the policy of the unit for management of infection in neutropenic patients, unless otherwise stated (see Table II). Antibiotic levels in serum were maintained within the therapeutic range in all patients in Group 2. Cultures were repeated on days 3, 7, 10 and 14 after omission of a single dose of amikacin and substitution with ‘Hepsal’, which was allowed to dwell within the catheter for 8 h prior to culture. Treatment was continued until cultures were reported as sterile. Cultures were again checked (a) immediately prior to discontinuing antibiotic, (b) 1 week after completion of treatment, and surveillance cultures were also performed at different time intervals within 6 weeks of completion of antibiotic therapy. The catheter tip was cultured on removal in all instances: tips were rolled on the surface of a chocolate agar plate (7% heated horse blood in Oxoid Columbia agar base cm 331) and incubated in 10% CO, at 37°C. The outside of the tips were then wiped with a sterile alcohol impregnated swab and placed in cooked meat broth (Mast 120) and incubated at 37°C for 24 h. Subcultures were incubated in 10% CO,. Results
A total of 16 organisms were cultured over the study period: nine were Gram-negative bacilli, five were Gram-positive cocci, one a Gram-negative
2
1
fluid
faecalis
pneumoniae
Staphylococcus epidermidis (3 isolates) Staphylococcus epidermidis Staphylococcus epidermidis
Enterococcus faecalis Serratia liquefaciens Enterobacter cloacae Aeromonas sp. Staphylococcus aureus
Klebsiella
Corynebacterium sp. Veillonella sp . Klebsiella pneumoniae Klebsiella pneumoniae Viridans streptococcus Acinetobacter sp. Klebsiella pneumoniae Escherichia coli Citrobacter freundii Enterococcus faecalis Citrobacter freundii Enterobacter sp.
Enterococcus
Broviac blood
according
sp
ND
(1 isolate) S. epidermidis
(1 isolate) S. epidermidis S. epidermidis
S. epidermidis
S. aureus
Bacillus
amikacin( 3); erythromycin(4) amikacin
amikacin
amikacin
amikacin(4); ampicillin( 10)
amikacin
-
ND
amikacin
-
12)
Antibiotics
amikacin(2)*; ampicillin(7) amikacin
Local
infections
amikacin amikacin(2); cefotaxime( amikacin amikacin amikacin
-
-
blood
catheter
S. epidermidis
E. faecalis S. liquefaciens Ent. cloacae Aeromonas sp. S. aureus
K. pneumoniae
site
of Broviac
Peripheral
to culture
K. pneumoniae K. pneumoniae Viridans streptococcus Acinetobacter sp. K. pneumoniae E. coli C. freundii E. faecalis C. freundii Enterobacter sp.
Broviac
findings
- = No organism isolated, ND = not done. * ( ) Duration of antibiotic (days). t - =No therapy given.
11
7
6
4 Cc)
3 (a)
Group 2
10
i 9
4 (a) 4 (b)
3 (b)
Group 1
Patient No.
Culture
TABLE I I. Details
+
piperacillin amikacin piperacillin amikacin
+
+
piperacillin + amikacin + flucloxacillin -
ampicillin
piperacillin amikacin
-t
Systemic
10
7
7
10
14
7
7
7” 10
14 14
9 14
Duration of treatment (days)
F;
Antibiotics
and Broviac
catheter
infection
113
coccus and one a Gram-positive bacillus (Table II). In eight of 14 episodes one species was grown, two species grew in each of two episodes, two had three species while in one episode four different organisms were grown. All Broviac infections were treated empirically with amikacin until sensitivities were reported at 48 h. Three species isolated from different episodes of infection (Enterococcus fuecalis, a viridans streptococcus and Staphylococcus epidermidis) (patients 1, 4b, 3a and 7, Table II) were resistant to amikacin and subsequent choice of antibiotic was dictated by antibiotic sensitivity pattern (Table II). Nine infective episodes were treated with intra-catheter antibiotic only, i.e. all patients in Group 1 and patient 6 in Group 2. In the latter patient, Staphylococcus epidermidis was cultured from an initial peripheral blood sample only; the patient was clinically well at the time and not neutropenic. It was considered appropriate to defer systemic treatment and Broviac catheter cultures were sterile 5 days after local treatment. Amikacin levels in peripheral blood were performed in three patients in Group 1 and none was detected. All remaining infections were additionally treated with systemic antibiotics. In the infective episode (a) of patient 3 a Bucillus sp. was recovered from peripheral blood, which had not been recovered from Broviac fluid or blood cultures. This patient was not neutropenic and was also clinically well; the organism was sensitive to ampicillin which was subsequently given as systemic treatment. The average time taken to obtain the first negative culture was 8 days (range 5-12 days). Treatment was continued 48 h after cultures became negative in all cases. All cultures were sterile 1 week after completion of antibiotic therapy and follow-up cultures over a 6-week period remained negative. Three patients developed a further Broviac infection (patients nos. 3, 4 and 6); the interval between first and second infection in patient 3 was 10 weeks, intervals to second and third infections in patient 4 were both 13 weeks. Klebsiellu pneumoniue was one of two organisms isolated in Broviac catheter fluid in the second episode in patient no. 4; although typing was not performed, the antibiotic sensitivity pattern was similar to that of the isolate obtained in the initial infection. As both isolates were sensitive to cefotaxime, intra-Broviac treatment with amikacin was discontinued after 48 h. Seven weeks after initial infection, patient no. 6 grew S. epidermidis in Broviac fluid, sensitive only to vancomycin. This was not treated further as therapy had been completed and a decision to remove the catheter was made. The tip of the catheter, not surprisingly, also grew S. epidermidis (see Table III). S. epidermidis was isolated from the tips of two other Broviac catheters on removal; both patients had previously had S. epidermidis catheter infections which, in each case, was treated with intra-Broviac amikacin. Through a laboratory oversight, sensitivity of S. epidermidis to amikacin was not tested
J. S. Rao et al.
114 TABLE III. Patient
No.
Group
1
Reason for removal Broviac catheter
Completion of Completion of Not removed Not removed Completion of Completion of Died; Broviac Died; Broviac
69; 95 150 159
2 1:
7 11
Duration of catheter life following antibiotic treatment (days) 122 127 99
: (b) 4 (4 (b)
Group 2 3 (4 ; (cl
Follow-up of Broviac catheter usefollowing antibiotic therapy of
Catheter tip culture on removal
treatment treatment
Sterile Sterile
treatment treatment in situ
Sterile Sterile
in situ
2 114 70 120
Completion Not removed Completion Completion Completion Completion
2:; 140
of treatment of of of of
treatment treatment treatment treatment
Sterile Sterile
S. epidermidi? S. epidermidis S. epidermidis
- = Not performed. *=See Results, fourth paragraph.
in one patient (no. 7); the organism was, however, resistant to gentamicin but sensitive to erythromycin and piperacillin. Intra-Broviac treatment was changed to 40 mg erythromycin (erythromycin lactobionate 1 g 20 ml-‘, Abbott) until eradication of infection, and systemic treatment with piperacillin and amikacin was continued for 7 days. Staphylococcus epidermidis in patient no. 11 was sensitive to amikacin and this patient was also treated with systemic amikacin and piperacillin. Broviac exit sites remained clinically uninfected in all patients throughout the study period. A positive exit site culture was, however, obtained in three patients at the time of Broviac catheter infection: patients 1 and 6 grew S. epidermidis and patient 5 Acinetobacter sp. All three patients were treated with intra-Broviac antibiotic only and the exit sites were cleaned with 0.5 % w/v chlorhexidine gluconate (‘Hibidil’, ICI Pharmaceuticals). Follow-up cultures after completion of treatment were negative in all patients. The catheters remained in use from 51 to 249 days (mean 118 days) following successful treatment of intra-Broviac infection (Table III). All catheters remained in situ until completion of treatment or until death from progression of the underlying disease. Discussion
There is no consensus on the nor the management catheters,’
approach to maintenance of Broviac of Broviac catheter infection.2-4 As
Antibiotics
and Broviac
catheter
infection
115
intracatheter infection is the predominant infectious complication experienced in this unit, the study was restricted to these patients. Schwartz et al., 6 in an innovative approach to prevention of intra-Broviac infection, showed that incorporation of vancomycin into heparin flushes reduced the incidence of infection with vancomycin sensitive organisms compared with a control group. Flynn et al., 4 in a study of treatment of catheter related infection by in-situ administration of antibiotics, i.e. systemic antibiotics through the infected line, concluded that ‘further improvement in management of patients with catheter related bacteraemia might be achieved by lengthening the time that antibiotic solutions dwell within the catheter.’ It would therefore appear that this study is a natural progression from that of Flynn et al., who were successful in eradicating Broviac related infection in 65% of patients. As Gram-positive cocci have, in previous series, been the predominant organisms associated with Broviac catheter infection2 the choice of amikacin for treatment merits clarification: vancomycin was initially explored as the antibiotic of choice but had to be abandoned because of incompatibility, at least in the authors’ hands, with heparinized saline solution. This is in contrast to the experience of Schwartz et aL6 who experienced no such incompatibility owing, most likely, to considerably lower doses of vancomycin (25 ltg ml-‘) and heparin (1 unit hep ml-‘). The broad antibacterial spectrum of activity of amikacin, on the other hand, which includes Gram-positive cocci, has made it the agent of choice in many life-threatening infections. By exposure of organisms to amikacin over a prolonged period of time at a concentration many times the minimum inhibitory concentration, activity against less sensitive organisms might be enhanced. The predominance of Gram-negative infections in this study may also be a major factor responsible for success in eradicating most infective episodes. Two infections were due to streptococci, and both isolates were resistant to amikacin which, given its limited activity against this group of organisms, is not surprising. Three infections caused by S. epidermidis, also grew S. epidermidis from the catheter tip on removal. While one of these infections had not been treated prior to catheter removal (patient no. 6, Table III), intervals of 249 and 140 days respectively elapsed from eradication of infection to removal of catheter in the other two patients, and random cultures in the interim had also been sterile. In the light of our experience, we would recommend that (a) amikacin be the antibiotic of first choice when intra-Broviac treatment only is considered, (b) if Gram-positive organisms are isolated, therapy may be changed as antibiotic sensitivity tests dictate and (c) where S. epidermidis is isolated, the incorporation of streptokinase into the catheter flush might remove the infected microthrombi which may be associated with S. epidermidis infections because of the production of polysaccharide slime by the organism. Quantitative cultures have recently been reported as useful in diagnosing
J. S. Rao et al.
116
catheter-related infection7 but these have been found to be of little value in the management of Broviac catheter-related sepsis.2 While they were not performed in this study, the rigid adherence to differential Broviac culture enabled a diagnosis to be made with confidence. Antibiotic was discontinued when 48-h cultures were reported sterile; follow-up cultures 1 week and 6 weeks after discontinuing antibiotic therapy were negative in all instances. This data would appear to indicate that the need for up to 2 weeks further antibiotic therapy following clearance of Broviac infections, as others have advocated,2 may well be unnecessary with the possible exception of S. epidermidis infection. While it is obvious to some, it nevertheless is important to emphasize that this approach to treatment of Broviac catheter infection should be restricted to carefully selected non-neutropenic patients. Where intravenous antibiotics were given, administration was through a peripheral vein in all instances so that bias could not be introduced. The authors would now recommend that for patients requiring systemic antibiotics, such as those categorized as Group 2 in this study, administration through the Broviac catheter is appropriate, followed by local instillation of antibiotic as stated. In conclusion, eradication of intra-Broviac infection is achievable by in-situ local treatment in carefully selected patients. Amikacin would appear to be an appropriate first-line antibiotic, but an alternative may be necessary in Gram-positive infections. Treatment can be administered on an outpatient basis. Catheter life is prolonged and inconvenience to family and hospital personnel is minimized. Financial savings are also an added benefit. We would like to thank Dr R. Hone, Clinical Microbiologist, Mater Hospital, Dublin, reviewing the paper, the nursing staff of our oncology ward for their co-operation vigilance and 0. Reddy for secretarial assistance.
for and
References 1. Reilly 2. 3. 4.
2: 7.
JJ, Steed DL, Ritter PS. Indwelling venous access catheters in patients with acute leukemias. Cancer 1984; 53: 219-223. Decker MD, Edwards KM. Central venous catheter infections. Ped Clin N Am 1988; 35: 579-605. Dickinson GM, Bisno AL. Infections associated with indwelling devices: infections related to extravascular devices. Antimicrob Agents Chemother 1989; 33: 602-607. Flynn PM, Shenep JL, Stokes DC, Barrett FF. In-situ management of confirmed central venous catheter related bacteremia. Pediatr Infect Dis J 1987; 6: 729-734. Clarke J, Cox E. Heparinisation of Hickman catheters. Nursing Times 1988; 84: 52-53. Schwartz C, Henrickson KJ, Roghmann K, Powell K. Prevention of bacteremia attributed to luminal colonisation of tunneled central venous catheters with vancomycin-susceptible organisms. J Clin Oncol 1990; 8: 1591-1597. Raucher HS, Hyatt AC, Barzilai A et al. Quantitative blood cultures in the evaluation of septicemia in children with Broviac catheter, J Ped 1984; 104: 29-33.