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Prophylactic antibiotics for preventing Gram positive infections associated with long-term central venous catheters in oncology patients

  1. Marianne D van de Wetering1,*,
  2. Job BM van Woensel2,
  3. Theresa A Lawrie3

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 25 NOV 2013

Assessed as up-to-date: 28 JUN 2013

DOI: 10.1002/14651858.CD003295.pub3


How to Cite

van de Wetering MD, van Woensel JBM, Lawrie TA. Prophylactic antibiotics for preventing Gram positive infections associated with long-term central venous catheters in oncology patients. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD003295. DOI: 10.1002/14651858.CD003295.pub3.

Author Information

  1. 1

    Emma Children's Hospital/Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

  2. 2

    Emma Children's Hospital / Academic Medical Centre, Pediatrics, Amsterdam, Netherlands

  3. 3

    Royal United Hospital, Cochrane Gynaecological Cancer Group, Bath, UK

*Marianne D van de Wetering, Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, PO Box 22660, Amsterdam, 1100 DD, Netherlands. m.d.vandewetering@amc.uva.nl.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 25 NOV 2013

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Characteristics of included studies [ordered by study ID]
Barriga 1997

MethodsDouble blind randomisation


ParticipantsN = 83 adults and paediatric patients with various malignancies, mainly leukaemia; 143 febrile episodes recorded


InterventionsVancomycin/heparin versus heparin-only flush (25 ug/ml vanco and 25 units/ml heparin)


Outcomes*Bacteraemia (BSI)
*Vanco-sensitive organism bacteraemia


NotesA difference was stated in neutropenia and non-neutropenia


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Daghistani 1996

MethodsDouble blind randomisation


ParticipantsN = 61 adult and paediatric patients
Various malignancies


InterventionsVancomycin/amikacin/heparin flush (25 ug/ml vanco, 25 ug/ml amikin and 100 units/ml hep) versus heparin only flush


Outcomes*Catheter-related sepsis (BSI)
*Cellulitis


NotesThe only study in which amikacin was added


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Di Carlo 2011

MethodsConsecutive people randomised; allocation by sealed envelopes


ParticipantsN = 108 adult patients receiving a TID (Port-a-cath) to facilitate chemotherapy


InterventionsCeftazidime (1g IVI 10 min before skin incision) versus no antibiotic (control)


Outcomes*Surgical site infections (superficial and deep)

*Infection considered if T°>37.5°C, WCC >10x10/L, and one or more of: pain, swelling, redness, or heat


NotesOutcomes assessed for 30 days after insertion


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear; method of randomisation not described; allocation by sealed envelopes; not blinded

Handrup 2013

MethodsOpen-label RCT; computer generated randomisation code in blocks of 20


Participantsn = 112 children aged 0-19 years receiving a newly placed TCVC to facilitate chemotherapy (49% haematological, 51% solid tumours)

129 TCVCs inserted, including 113 TIDs and 16 TCVCs with external lines (TEs)


InterventionsTaurolidine/heparin/sodium citrate lock solution versus heparin lock solution


Outcomes*CRBSI

*Exit-site and tunnel infections

*Mechanical complications


NotesFollowed up (catheters in situ) from 12 to 1176 days

Type of CVC was a risk factor for CRBSI (TIDs were less likely to get infected than TEs)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Henrickson 2000

MethodsDouble blind randomisation
Stratified for risk groups


ParticipantsN = 126 paediatric patients (44% ALL, 40% solid, 7 % BMT). There were 153 assessable TCVCs


InterventionsVancomycin/heparin versus heparin only flush (25 ug/ml vanco and 100 units/ml heparin)


Outcomes*Exit-site infection
*Bacteraemia (CRBSI)
*Time to first infection


NotesThe third group included vanco/heparin ciprofloxacin

Quantitative cultures were done


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Lim 1993

MethodsMethod of randomisation not clear


ParticipantsN = 88 adult oncology patients with haematological malignancies

Baseline characteristics reported - no significant difference


InterventionsTeicoplanin before insertion 400 mg before insertion catheter versus control


Outcomes*Soft tissue infection
*Catheter-related sepsis (CRS)


NotesAll episodes of CRS occurred in people who were neutropenic


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Ljungman 1997

MethodsMethod of randomisation not clear


ParticipantsN = 66 adult oncology patients, BMT and leukaemia patients


InterventionsTeicoplanin prior to insertion and 24 hrs after insertion


Outcomes*Bacteraemia (BSI)
*Exit-site infection


NotesAt interim analysis, the pre-set efficacy could not be met, therefore they stopped study


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Rackoff 1995

MethodsDouble blind randomisation


ParticipantsN = 55 paediatric patients, one centre (total group was 63 patients, 8 were receiving TPN)
Analysis was done on the oncology patients only


InterventionsVancomycin/heparin versus heparin only flush
(25 ug/ml vanco and 100 units/ml heparin)


Outcomes*Bacteraemia with a vanco sensitive organism (CRBSI)
*Time to first infection


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Ranson 1990

MethodsDouble blind randomisation


ParticipantsN = 98 adults
A) N = 48 and 35 catheters, acute leukaemia and BMT
B) N = 50 and 37 catheters (solid tumour)


InterventionsVancomycin versus control (2 doses one prior to insertion, one after positioning of the catheter)
500 mg vanco


Outcomes*Catheter-related sepsis in first 30 days
*Tunnel sepsis
*Coagulase negative staphylococcal bacteraemia


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Schwartz 1990

MethodsDouble blind randomisation


ParticipantsN = 45 paediatric patients


InterventionsVancomycin/heparin versus heparin only flush (25 ug/ml vanco and 100 units/ml heparin)


Outcomes*Bacteraemia (quantitative culture)
*Time to first infection


NotesStatistics on the number of children not catheters

Quantitative blood cultures


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Vassilomaniakis 1995

MethodsRandomisation by cards in closed envelopes


ParticipantsN = 40 adult patients


InterventionsVancomycin versus control
(vanco in 3 doses of 500 mg 1 hr prior to insertion, 6 and 12 h afterwards)


Outcomes*Exit-site infection
*CRBSI
*Gram positive infections


NotesOnly initially randomised


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abdelkefi 2005An RCT of low-dose heparin prophylaxis not antibiotic prophylaxis to reduce non-tunnelled CVC-related infections in haemato-oncological disease

Akyuz 2012RCT of taurolidine lock solution versus heparin lock solution in children undergoing treatment for cancer. This study did not specifically include patients with newly inserted TCVCs

Al Sibai 1987146 patients with malignant disease received 160 Hickman catheters. 70 of these patients received prophylactic antibiotics during and after insertion of the catheter. The catheter infection rate dropped from 0.5-0.25 per 100 days. Excluded because the antibiotic use and duration were at the discretion of the attending physician, and the results were retrospectively analysed

Carratala 1999Adult haematology patients with non-tunnelled CVC's received 10 U heparin per ml (N = 57) or 10 U heparin + 25 µg vancomycin per ml (N = 60) allowed to dwell in catheter 1 hour every 2 days. Catheter-related bacteraemia in 7% of people in control group and 0% in experimental group (P = 0.05).
Mainly excluded because non-tunnelled catheters

Chambers 2005RCT of sustained release chlorhexidine dressings (not antibiotics) versus standard dressings for TCVCs in neutropenic people

Chatzinikolaou 2003aProspective cohort study. M-EDTA was used as lock solution in indwelling ports in 14 children. No catheter-related infections were observed. In 48 control participants locked with heparin 10 port infections were observed.
Not included because cohort study

Chatzinikolaou 2003bHaemodialysis catheters in people with cancer. 66 people impregnated catheters with minocycline and rifampin and 64 non-impregnated catheters. 0 catheter-related infections in the impregnated group and 7 in the non-impregnated group, duration catheter 8 days. Excluded because this concerns non-tunnelled catheters and the duration of insertion was short

Dawson 2000143 paediatric oncology patients, with 176 TCVC. Intervention cephalothin 100 mg/kg iv or vancomycin 20-25 mg/kg iv prior to insertion of the catheter. Rate of infections <30 days dropped 40%.
No randomisation performed and intervention period was compared to pre-intervention period

Dumichen 2012RCT of taurolidine citrate versus heparin as a catheter lock solution in 71 paediatric oncology patients. The lock solution was not used immediately after TCVC insertion in most participants (given up to 2 months after insertion in some cases)

Ferreira Chacon 2011RCT of minocycline/EDTA versus heparin lock solution in children with TCVCs for chemotherapy, however TCVCs were not newly placed

Fourcade 2001Prospective cohort study using antibiotic lock technique to prevent bacteraemia in chronic haemodialysis catheters. The incidence of bacteraemia dropped from 4.6 per 1000 catheter days to 0.88 per 1000 catheter days.
Not RCT, comparison with historical control, non-tunnelled catheters

Garland 2005Prospective RCT in critically ill neonates. Vanco lock solution was used in 42 infants and heparin lock in 43 infants. Two people in the vanco/heparin lock group developed a catheter-related infection, 13 people in the control group developed a catheter-related infection, RR 0.13 (95% CI 0.01 to 0.57) highly significant, duration catheter 20 days. Excluded because it concerns non-tunnelled catheters and done in neonates, which is not the appropriate group for our inclusion criteria

Hanna 2004Prospective RCT at MD Anderson in cancer patients, 356 catheters placed, 182 impregnated with minocyclin and rifampin, 174 non-impregnated. Mean duration of the catheter 66 days. Three catheter-related infections in the MR group and 14 in the non-impregnated group, highly significant. Not included because these are non-tunnelled catheters and baseline risk for these catheters is higher than the tunnelled catheters. Also, we included studies of newly inserted tunnelled central venous catheters only

Hitz 2012RCT of TCVCs coated with athrombogenic coating versus no coating in cancer patients, not an RCT of prophylactic antibiotics

Jaeger 2005RCT of chlorhexidine/sulfadiazine impregnated CVCs versus standard CVCs in leukaemia patients. This study did not use tunnelled catheters

Ocete 1998Single-centre trial; 2 groups control group - 61 newborns and experimental group 85 newborns, all receiving a central catheter (umbilical artery, umbilical vein and/or silastic). The study group received prophylactic vancomycin 25 ug/ml. All participants received parenteral nutrition. Results CNS 21/61 in the control group and 19/85 in the vancomycin group (P < 0.05). The patient group is not the group studied in this review. Methods of the study poor. Not specified how often the prophylactic vanco was given. Clinical criteria were used to determine if the neonate was infected, and then peripheral and central cultures were done. Not specified if quantitative or qualitative cultures were done. Trial not blinded, no tunnelled catheters used, inappropriate patient group

Raad 1998Crossover study: 26 people with melanoma on IL2 treatment enrolled. All people received a double lumen non-tunnelled silicone catheter in subclavian vein. People randomised to receive prophylactic antibiotics novobiocin 500 mg + rifampin 300 mg orally. Significant results 41% in control group catheter-related bacteraemia and 6% in experimental group, excluded because of non-tunnelled catheters.
Very specific group with high incidence of infection, not representative of the participant group for this Cochrane review

Raad 2005RCT evaluating dalbavancin versus vancomycin for the treatment of adults with CRBSIs

Rubie 1995163 paediatric patients with cancer had 180 subcutaneous ports inserted. Over time a change of policy was made from only flushing with heparin to a V/H solution. The infection rate dropped from 31% to 4%. This study was not randomised and the results were retrospectively analysed

Scaife 2010A retrospective study of perioperative antibiotic prophylaxis for TCVCs implanted to facilitate chemotherapy in adults

Schierholz 2010RCT evaluating an antibiotic-releasing CVC (rifampicin-miconazole) versus a standard CVC in adults (38% with cancer). Non-tunnelled CVCs were compared

Simon 2008Not a RCT. A prospective cohort study of heparin versus taurolidine lock solution in 188 adults receiving chemotherapy for cancer. The taurolidine lock solution significantly reduced the rate of CRBSIs

 
Comparison 1. Antibiotics prior to long-term CVC insertion versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Catheter-related sepsis5360Risk Ratio (M-H, Random, 95% CI)0.72 [0.33, 1.58]

    1.1 Vancomycin
299Risk Ratio (M-H, Random, 95% CI)0.46 [0.07, 3.20]

    1.2 Teicoplanin
2153Risk Ratio (M-H, Random, 95% CI)0.84 [0.25, 2.91]

    1.3 Ceftazadime
1108Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Antibiotic and heparin flush or lock solution versus heparin only

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Catheter-related sepsis6468Risk Ratio (M-H, Random, 95% CI)0.47 [0.28, 0.80]

    1.1 Vancomycin
4275Risk Ratio (M-H, Random, 95% CI)0.48 [0.24, 0.94]

    1.2 Vancomycin and amikacin
164Risk Ratio (M-H, Random, 95% CI)0.76 [0.14, 4.22]

    1.3 Taurolidine
1129Risk Ratio (M-H, Random, 95% CI)0.39 [0.15, 1.03]

 
Summary of findings for the main comparison. Summary of findings: prophylactic antibiotics before long-term CVC insertion

Antibiotics compared with no antibiotics prior to long-term CVC insertion to prevent catheter-related infections

Patient or population: adults with a newly inserted long-term CVC who were at risk of neutropenia due to chemotherapy or disease

Settings: inpatient and outpatient

Intervention: intravenous antibiotics (vancomycin, teicoplanin or ceftazidime)

Comparison: placebo or no antibiotics

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAntibiotics

Catheter-related sepsis 200 per 1000144 per 1000
(66 to 316)
RR 0.72 (0.33 to 1.58)360
(5)
⊕⊕⊕⊝
moderate
The difference between the comparison groups was not significant (P = 0.41). We downgraded this evidence to moderate due to the substantial heterogeneity (I² = 52%) between studies.

*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Summary of findings 2. Summary of findings: antibiotic and heparin versus heparin only flush or lock solution

Antibiotic and heparin solution compared with a heparin only solution for flushing or locking long-term CVCs to prevent Gram positive catheter-related sepsis

Patient or population: adults and children with a newly inserted long-term CVC who were at risk of neutropenia due to chemotherapy or disease

Settings: inpatient and outpatient

Intervention: antibiotic (vancomycin, vancomycin and amikacon, or taurolidine) plus heparin solution

Comparison: heparin only solution

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Heparin-onlyAntibiotic/heparin

Catheter-related sepsis200 per 100094 per 1000
(56 to 160)
RR 0.47 (0.28 to 0.80)468
(6)
⊕⊕⊕⊝
moderate
Data consistent across included studies; I² = 0%; P = 0.005. For an assumed risk of 15%, the NNT = 12 (9 to 33). We downgraded this evidence to moderate as the sample was clinically heterogeneous.

*The basis for the assumed risk is the mean control group risk across included studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; NNT: number needed to treat

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Table 1. Criteria for the assessment of methodological quality of included studies

Item IDDescriptionImplementation

Patient selectionNote: all criteria were scored yes (+), no (-) or don't know

aWere the eligibility criteria specified?Patient inclusion/exclusion criteria must have been described appropriately according to the reviewer

b1Was a method of randomisation applied?A random (unpredictable) allocation must have been applied

b2Was the treatment allocation concealed?Allocation should have been performed by an independent person not responsible for determining eligibility for inclusion.

cWere the groups similar at baseline with regard to the most important prognostic indicators?Groups must be similar at baseline with regard to at least three of the four prognostic indicators of age sex duration of symptoms and value of main outcome measures

Intervention

d1Was the experimental intervention explicitly described?Adequate description of the experimental intervention so that treatment can be replicated

d2Was the control intervention explicitly described?Adequate description of the control intervention so that treatment can be replicated

eWere co-interventions avoided or similar for all groups?Co-interventions should either have been avoided in the trial design or be similar in the 2 groups

fWas the patient blinded for the intervention?Adequate information about blinding must have been provided

Outcome measurement

gWas the outcome assessor blinded to the intervention?Adequate information about blinding must have been provided

hWere the outcome measures relevant?At least one of the following outcome measures must be included: catheter-related sepsis, exit infections, tunnel infections and time to first infection

iWere complications described?Any adverse events should be noted

jWas the dropout loss to follow up described and acceptable?Included people who did not complete the follow up period or were not included in the analysis should be described, if the percentage of dropouts is less than 20% then a '+' is scored

kWas a follow-up measurement performed?Outcome assessment after randomization

lWas the timing of the outcome similar for all groups?Timing of outcome assessment should have started from the moment of treatment allocation and be identical for all intervention groups and all important outcome measures

S tatistics

mWas the sample size described for each group?Sample size should have been presented for each group at randomisation and for the most important outcome measures

nDid the analysis include an intention-to-treat analysis?For all randomised people the most important moments of effect measurement should have been reported

oWere point estimates and measures of variability presented for the primary outcome measures?For continuous data mean, median, standard deviation with 95 % confidence interval should be presented. For nominal and ordinal outcomes the number of people to whom the outcome measure applies and the total number of people must be presented


 
Table 2. Internal validity scores (b1, b2, c, e, f, g, j, l, n)

referenceb1b2cefgjln

Vassilomaniakis 1995+-++--+++

Ranson 1990++++++?+++?

Lim 1993+-++-+?+++

Barriga 1997+++++++++

Rackoff 1995+++++++++

Schwartz 1990+++++++++

Henrickson 2000+++++++++

Daghistani 1996++++++?+++

Ljungman 1997+-----+++

Di Carlo 2011++++--++?

Handrup 2013+-++--+++

 
Table 3. External validity (a, d1, d2, h, i, k, m, o)

Referencead1d2hikmo

Vassilomaniakis 1995++++?-+++

Ranson 1990++++?-+++

Lim 1993++++-++-

Barriga 1997++++-+++

Rackoff 1995++++-+++

Schwartz 1990++++-+++

Henrickson 2000++++-+++

Daghistani 1996++++-+++

Ljungman 1997++++-+++

Di Carlo 2011++++-+++

Handrup 2013++++-+++