J Antimicrob Chemother 2010; 65: 525 – 530

doi:10.1093/jac/dkp499 Advance publication 18 January 2010

Evaluation of linezolid, vancomycin, gentamicin and ciprofloxacin in a

rabbit model of antibiotic-lock technique for Staphylococcus aureus
catheter-related infection
Nuria Fernández-Hidalgo1,2*, Joan Gavaldà1,2, Benito Almirante1,2, Marı́a-Teresa Martı́n1,2, Pedro López Onrubia1,2,
Xavier Gomis1,2 and Albert Pahissa1,2

Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020

1
Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 2Faculty of Medicine, Universitat Autònoma de
Barcelona, Barcelona, Spain

*Corresponding author. Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain. Tel: þ34-932746090;
Fax: þ34-934894091; E-mail: nufernan@gmail.com

Received 16 September 2009; returned 4 November 2009; revised 14 December 2009; accepted 20 December 2009

Background: The effectiveness of linezolid, vancomycin, ciprofloxacin and gentamicin for treating experimental
Staphylococcus aureus catheter-related infection by the antibiotic-lock technique was assessed.
Methods: Two methicillin-susceptible (MSSA) ATCC strains and two methicillin-resistant (MRSA) clinical strains
were used. New Zealand white rabbits were surgically implanted with a silicone intravenous catheter. Infection
was induced by filling and locking the catheter with 0.3 mL of broth culture containing S. aureus, with turbidity
equivalent to that of a 0.5 McFarland standard. Eighteen hours later the antibiotic-lock technique was started
and continued for 24 h. Treatment groups were: control without treatment; 2000 mg/L linezolid; 2000 mg/L
vancomycin; 2000 mg/L ciprofloxacin; and 40 000 mg/L gentamicin.
Results: Linezolid and vancomycin showed equivalent activity, achieving significant reductions in log10 cfu
recovered from catheter tips in one MSSA strain (.1.12) and one MRSA strain (.0.77) as compared with con-
trols (P,0.05). Ciprofloxacin achieved significant log10 cfu reductions in MSSA strains relative to controls
(.2.51, P,0.01). In one MSSA strain, ciprofloxacin showed a larger reduction in log10 cfu than linezolid or van-
comycin (P,0.01). Gentamicin was the only antibiotic achieving negative catheter tip cultures (up to 87.5% in
MSSA and up to 40% in MRSA, P,0.01), and showed the greatest log10 cfu reduction compared with controls
(.4.25 in MSSA and .2.93 in MRSA, P,0.05) and significant differences relative to the remaining treatment
groups (P,0.05 in both MSSA and MRSA).
Conclusions: Gentamicin showed the highest activity against both MSSA and MRSA biofilms.

Keywords: animal, stability, methicillin-susceptible, methicillin-resistant

Introduction evidence that catheter removal is the safest option in this

Catheter-related bacteraemia (CRB), an infection related to
biofilm formation, usually requires systemic antimicrobial
therapy and catheter removal. However, the loss of an access
vein, the need for a new procedure to replace the catheter and
the cost of catheter replacement all argue in favour of attempt-
ing to salvage the infected line when the clinical situation allows
it. Antibiotic-lock therapy (ALT) combined with a conventional
systemic antibiotic has proved to be effective treatment for long-
term CRB, particularly in episodes caused by Gram-negative
bacilli and coagulase-negative staphylococci.1,2
However, it is much more difficult to apply conservative treat-
ment in Staphylococcus aureus infections. There is substantial
subgroup of cases, since previous studies have shown a failure
rate up to 45% –59%,1,3 and some deaths have been reported1,4
with conservative management. Hence, it is generally accepted
that a conservative approach to S. aureus CRB with ALT and sys-
temic treatment should be avoided. Nevertheless, ALT has been
considered a viable option in selected cases, particularly in non-
neutropenic, haemodynamically stable patients with no other
vascular access, in whom transoesophageal echocardiography
has ruled out infective endocarditis,5 and under very close
follow-up.
There are no clinical trials investigating treatment of S. aureus
CRB with the antibiotic-lock technique, and few experimental
studies have compared different antimicrobials for conservative

# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org

525
Fernández-Hidalgo et al.
management of S. aureus catheter-related infection.6,7 Vanco-
mycin is the most widely used antimicrobial for treating the
few clinical cases of long-term S. aureus CRB described in the
literature.1 – 3,8 Linezolid, a bacteriostatic antimicrobial with
good activity against methicillin-resistant S. aureus (MRSA),
could be a feasible therapeutic alternative in CRB episodes
caused by this microorganism, which have increased in our
setting.9 Ciprofloxacin, although active against some methicillin-
susceptible S. aureus (MSSA), has been used only sporadically to
treat Gram-negative episodes of CRB.1,8 Finally, gentamicin has
also been used for treating catheter-related bacteraemia due
to Gram-negative rods.1,8,10 – 12 As is the case of ciprofloxacin,
although the bactericidal activity of gentamicin against MSSA
and MRSA is well recognized, to our knowledge its use as
antibiotic-lock for treating S. aureus catheter-related infections
in humans has not been reported in the literature.
The aim of this study was to evaluate the activity of linezolid,
vancomycin, ciprofloxacin and gentamicin for the treatment of
experimental S. aureus catheter-related infection by means of
the antibiotic-lock technique.
Materials and methods
Antimicrobial stability studies
To investigate the stability of the drugs tested, commercial solutions con-
taining 2000 mg/L linezolid (Pfizer S.A., Alcobendas, Spain), 2000 mg/L
vancomycin (Laboratorios Normon S.A., Tres Cantos, Spain), 2000 mg/L
ciprofloxacin (Quı́mica Farmacéutica Bayer, Barcelona, Spain) and
40000 mg/L gentamicin (Laboratorios Normon S.A., Tres Cantos, Spain)
were prepared aseptically following the manufacturer’s instructions in
the same way as those prepared in clinics for treating catheter infection
with antibiotic-lock.
Antibiotic solutions were placed in sterile glass tubes and incubated
at 378C in the dark at room atmosphere. Samples were obtained
sequentially in triplicate at 0, 24 h, 72 h, 7 days and 10 days,
and frozen at 2808C until analysis. Vancomycin and gentamicin
concentrations were determined by immunofluorescence assay (AxSYM
Analyzer, Abbott Laboratories, Chicago, IL, USA). The sensitivity of the
assay was 1.25 mg/L and the coefficients of variation were ,7%. Cipro-
floxacin determinations were carried out by the disc plate bioassay
method13 using Klebsiella pneumoniae (ATCC 10031) as the test micro-
organism in antibiotic medium 5 (Difco Laboratories, Detroit, MI, USA).
Standard curves were determined with ciprofloxacin solutions (0.15,
0.3, 0.5, 0.7 and 0.9 mg/L) in rabbit serum (Sigma-Aldrich, Madrid,
Spain). The standard samples were assayed five times, and test
samples were assayed in triplicate. The linearity (r 2) of the standard
curve was 0.95. The sensitivity of the assay was 0.15 mg/L, and the
between- and within-day coefficients of variation for replicates were
both 3%. Linezolid determinations were also carried out by the disc
plate bioassay method13 using Bacillus subtilis (ATCC 6633) as the test
microorganism in antibiotic medium 5. Standard curves were determined
with linezolid solutions (1, 4, 8, 12, 16 and 20 mg/L) in rabbit serum
(Sigma-Aldrich, Madrid, Spain). The standard samples were assayed in
quintuplicate, and test samples were assayed in triplicate. The linearity
(r 2) of the standard curve was 0.91. The sensitivity of the assay was
1 mg/L, and the between- and within-day coefficients of variation for
replicates were both ,3%.
Samples taken at every timepoint preserved their antibacterial
activity, as proved by the broth microdilution method following the
CLSI (formerly NCCLS) guidelines14 and using S. aureus ATCC 29213 as
test microorganism, with MICs similar to those of pure substances.
526
Strains
Two MSSA strains (ATCC 29213 and ATCC 6538P) and two clinical isolates
of methicillin- and ciprofloxacin-resistant S. aureus strains (MRSA 7 and
MRSA 16) were used. The ability of these strains to form biofilms was
assessed with the Crystal Violet technique using the method described
by Kamagata-Kiyoura et al. 15 with minor modifications.
Antimicrobial susceptibility studies
The MICs and MBCs of linezolid, vancomycin, ciprofloxacin and gentami-
Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020
cin for the strains studied were determined with the microdilution tech-
nique following CLSI recommendations.16
Animals
New Zealand white rabbits weighing 2.0– 2.2 kg were used for the in vivo
experiments. On their arrival, rabbits were housed in individual cages and
provided with water and food ad libitum throughout the experiments.
The experimental protocol was approved by the Ethics Committee for
Animal Experimentation of our institution and the Conselleria de Medi
Ambient de la Generalitat de Catalunya (Ministry of Environment of the
Catalan Government).
Catheter placement
Animals were anaesthetized by intramuscular injection of 100 mg/kg
ketamine plus 20 mg/kg xylazine. A right laterocervical incision was
made to expose the jugular vein bifurcation. The internal jugular vein
was distally ligated and catheterized with an 18 cm length of sterile sili-
cone tubing (SILASTIC, ID/OD: 0.45/0.77 inch, Dow Corning Corporation,
MI, USA). The catheter was inserted up to 8 cm, to ensure positioning
of the tip within the superior cava vein, and secured with silk sutures.
Patency was checked by drawing blood and flushing with sterile saline.
The line was subcutaneously tunnelled and brought to the interscapular
region. The external portion of the catheter was connected to a remov-
able hub (Vygon 1298.20, Laboratories Pharmaceutiques Vygon,
Ecoulen, France) attached to a disposable port (Sendal TP Inter Minisend,
UK) and fixed to the skin.
Catheter inoculation
After placement, catheters were filled with an S. aureus suspension pre-
pared as follows. The strain was subcultured in trypticase soy agar (TSA)
for 24 h. Colonies isolated from the subculture were suspended in trypti-
case soy broth (TSB) plus 0.5% dextrose and incubated in a shaking bath
until reaching a turbidity equivalent to that of a 0.5 McFarland standard
(108 cfu/mL); 0.3 mL of this suspension was used to fill the catheter. The
inoculum was locked in the lumen of the catheter and remained there
for 18 h.
Catheter treatment
Just before starting antibiotic-lock, the inoculum was carefully withdrawn
by aspiration. The disposable port and hub were replaced by new devices.
The catheter system was filled with 0.33 mL of antimicrobial solution or
sterile saline, as appropriate. Animals were randomized into the following
groups: controls receiving sterile saline; and animals receiving 2000 mg/L
linezolid, 2000 mg/L vancomycin or 40000 mg/L gentamicin. In the
MSSA experiments, a group treated with 2000 mg/L ciprofloxacin
was added. Sterile saline or antimicrobial solution was locked into the
catheter for 24 h.
Antibiotic-lock for S. aureus infection JAC
Efficacy studies susceptible to ciprofloxacin and, for these strains, ciprofloxacin
At the end of the treatment period, animals were euthanized by intra-
was bactericidal.
venous injection of sodium pentothal and catheters were removed
for microbiological evaluation using an aseptic technique. The distal
(intravenous) 4 cm of the catheter was cut for quantitative culture. The Antimicrobial stability studies
lumen of the catheter segment was gently flushed twice with 2 mL of
All the antibiotics tested were stable over the entire observation
sterile saline and the segment was then bisected lengthwise, submerged
in 4 mL of sterile saline and sonicated at 50 Hz for 10 min. Both the flush-
period. Ten days after preparation of the solutions, antibiotic con-
ing and sonication products were washed twice by centrifugation and the centrations were similar to the initial values (Table 2).
pellet was resuspended in sterile saline. After the second washing, the
pellet was suspended in 1 mL of sterile saline and serially diluted. To

Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020

ensure that all single viable cells could be recovered and counted,
small aliquots of the dilutions, as well as the remaining undiluted
volume, were plated in duplicate onto 5% sheep blood Columbia agar
plates and incubated for 48 h at 378C at room atmosphere. After incu-
bation, colony count was performed. Results were expressed as log10
total cfu.
Statistical analysis
For statistical purposes, catheters yielding a negative result were
recorded as having one colony. The percentage of negative cultures
obtained for each treatment arm was compared using Fisher’s exact
test, and the log10 cfu recovered from the catheter tips were compared
using the Mann–Whitney test. P values 0.05 were considered statisti-
cally significant.
Results
Antimicrobial susceptibility studies
The MIC/MBC of linezolid, vancomycin, ciprofloxacin and genta-
micin for the strains studied are shown in Table 1. Predictably,
linezolid was bacteriostatic for all the strains tested, while vanco-
mycin and gentamicin were bactericidal. Only MSSA strains were
Therapeutic experiments
Results obtained from catheter tip culture are shown in
Tables 3 and 4. The activities of linezolid and vancomycin against
S. aureus biofilm using the antibiotic-lock technique were
similar and strain dependent in all the experiments. As compared
with controls, linezolid and vancomycin locks achieved a signifi-
cant reduction in the log10 cfu recovered from catheter tips in
MSSA ATCC 29213 (2.01 and 1.12, respectively, P,0.05) and in
MRSA 7 (0.77 and 0.79, respectively, P,0.05). However, in
MSSA ATCC 6538P and in MRSA 16, there were no statistical
differences relative to controls.
As compared with controls, ciprofloxacin achieved a signifi-
cant reduction (.2.51 log10, P,0.01) in catheter tip log10 cfu
of MSSA strains. This reduction proved to be significantly
greater than with linezolid and vancomycin only for MSSA
ATCC 6538P (2.69 versus 0.71 and 0.67, respectively, P,0.01).
Gentamicin was the only antibiotic achieving a significant pro-
portion of negative catheter cultures in all the strains after 24 h
of antibiotic-lock: 63.6% and 87.5% in MSSA (P, 0.01 versus con-
trols); and 40% and 25% in MRSA (P,0.01 versus controls).
Moreover, the largest log10 cfu reduction was observed with gen-
tamicin in all the strains studied (.4.25 in MSSA and .2.93 in
MRSA), with statistical differences compared with controls and

Table 1. Susceptibility of the four study strains to linezolid, vancomycin, ciprofloxacin and gentamicin

Linezolid Vancomycin Ciprofloxacin Gentamicin

Strain MIC MBC MIC MBC MIC MBC MIC MBC

S. aureus ATCC 29213 2 .32 1 1 0.25 0.5 0.5 0.5

S. aureus ATCC 6538P 2 .32 0.5 2 0.25 0.5 0.25 0.25
MRSA 7 4 .32 1 2 .32 .32 0.5 0.5
MRSA 16 4 .32 1 1 .32 .32 0.5 0.5

For all the antimicrobials, MIC and MBC results are expressed as mg/L.

Table 2. Antimicrobial concentrations (mg/L) at different timepoints

0h 24 h 72 h 7 days 10 days

Linezolid 2203 (92) 1831 (164) 2013 (126) 2120 (79) 2487 (196)
Vancomycin 2150 (53) 2225 (56) 2176 (29) 2111 (34) 2096 (36)
Ciprofloxacin 1876 (76) 2252 (175) 1869 (154) 1885 (249) 2284 (68)
Gentamicin 40150 (2240) 40467 (2250) 41 067 (3871) 44567 (1722) 45 933 (1935)

Results represent the mean (SD) of three aliquots analysed simultaneously.

527
Fernández-Hidalgo et al.

Table 3. Results of treatment of MSSA experimental catheter-related vancomycin at 2500 mg/L and ciprofloxacin at 1000 mg/L
sepsis showed a similar cfu reduction compared with controls after
24 h of treatment in one of the two strains studied (2 log10,
S. aureus ATCC 29213 S. aureus ATCC 6538P P,0.05). In the second strain, only ciprofloxacin showed a sig-
nificant cfu reduction relative to controls and vancomycin
negative log10 total cfu negative log10 total cfu (2 log10, P,0.05).6 In another study involving a rat model of
Treatment cultures/total (SD) cultures/total (SD) MSSA central venous catheter-related infection, linezolid at
1024 mg/L showed a reduction of 2 log10 cfu as compared
Control 0/9 5.50 (1.89) 0/8 5.64 (1.32) with control animals, and its efficacy was improved by adding
Linezolid 1/8 3.49 (1.87)a 0/8 4.93 (0.59) the protegrin IB-367.17 Along the same lines, in a rat model of
Vancomycin 1/7 4.38 (1.91)a 0/9 4.97 (1.13) MSSA central venous catheter-related infection used by the

Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020

Gentamicin 7/11a 1.24 (1.35)a,b 7/8a 0.54 (0.66)c,d same group, ciprofloxacin and vancomycin (both 1024 mg/L)
Ciprofloxacin 0/8 2.98 (1.83)a 0/8 2.95 (1.50)c showed similar activity against S. aureus biofilm that improved
by adding RNAIII-inhibiting peptide.18 However, it is extremely
a
P,0.05 versus control. difficult to establish comparisons between these studies and
b
P,0.05 versus other groups of treatment. our experiments because of considerable differences in the
c
P, 0.01 versus control, linezolid and vancomycin. designs with respect to the S. aureus inoculum and susceptibility
d
P,0.01 versus ciprofloxacin. to methicillin, antibiotic volume and concentration, addition of
coadjuvant therapy, length of antibiotic-lock and duration of
the experiments, among other factors.
Table 4. Results of treatment of experimental MRSA catheter-related In our study, gentamicin was the only antibiotic resulting in
sepsis negative catheter cultures in all the strains studied (up to
87.5% in MSSA and up to 40% in MRSA) and was the drug achiev-
MRSA 7 strain MRSA 16 strain ing the greatest reduction in log10 cfu (.4.25 in MSSA and .2.93
in MRSA) after only 24 h of ALT. To our knowledge, there are
negative log10 total cfu negative log10 total cfu no experimental studies of S. aureus catheter-related infection
Treatment cultures/total (SD) cultures/total (SD) assessing the gentamicin-lock technique. However, in an
in vitro model of MSSA biofilm treated with several antimicro-
Control 0/15 5.90 (1.13) 0/9 5.94 (1.36) bials, only gentamicin proved to be effective in eradicating the
Linezolid 0/10 5.13 (0.94)a 0/12 4.64 (1.62) biofilm, whereas vancomycin and ciprofloxacin did not clear
Vancomycin 0/13 5.11 (1.05)a 0/13 5.00 (1.41) the staphylococci.19 Moreover, in another recent in vitro model
Gentamicin 4/10a 2.19 (1.78)a,b 2/8a 3.00 (2.67)a of MSSA and MRSA biofilms, 5000 mg/L gentamicin showed
better activity than 500 mg/L tigecycline or 1000 mg/L daptomy-
a
P,0.05 versus control. cin in terms of mean log10 cfu reduction at 24 h.20 One possible
b
P,0.01 versus linezolid and vancomycin. explanation for the weak activity of vancomycin could be its
reduced rate of penetration in S. aureus biofilm, as has been
demonstrated by confocal microscopy.21
the remaining treatment groups (P,0.05 in both MSSA and The differences in the activity of gentamicin between MSSA
MRSA strains). and MRSA strains cannot be explained by the present study
because the MICs of gentamicin for the four strains tested
were similar for planktonic bacteria. Thus, further in vitro
Discussion
studies focusing on the activity of S. aureus biofilm after exposure
This study assesses the effectiveness of linezolid, vancomycin, to gentamicin and other antibiotics are needed to elucidate this
ciprofloxacin and gentamicin for the treatment of experimental differing behaviour.
S. aureus catheter-related infection with the antibiotic-lock tech- S. aureus is one of the most important microorganisms
nique. Our results show that gentamicin had the highest activity associated with nosocomial infection originating in catheters
against both MSSA and MRSA strains, whereas the activities of and other prosthetic medical devices because of its ability to
linezolid and vancomycin were similar and significantly lower. form biofilms. Bacteria that attach to surfaces aggregate in a
For one of the MSSA strains, ciprofloxacin showed higher activity polymeric matrix which they synthesize, producing biofilms.
than linezolid or vancomycin. Formation of these sessile communities, which have an inherent
The few experimental studies published on ALT for S. aureus resistance to antimicrobial agents, is at the root of many
catheter-related infection are not strictly comparable to ours, persistent and chronic infections.22 Due to this resistance to
and none has assessed gentamicin; nevertheless, their results antimicrobials, it is extremely important to reach an effective
are similar in terms of antimicrobial activity. In a rat model of concentration of antibiotic locally at the treatment site. In our
MSSA central venous catheter-related infection, ALT with linezolid study, vancomycin, ciprofloxacin and linezolid were used at
showed a reduction in cfu counts similar to that achieved with 2000 mg/L, the concentration applied in ALT in our centre. For
vancomycin and ciprofloxacin after 7 days of treatment linezolid and ciprofloxacin (as for gentamicin at 40 000 mg/L)
(2 log10, P, 0.05). All these antibiotics were administered at this is also the concentration provided by the manufacturer in
1024 mg/L.7 Moreover, in a rabbit model of MSSA central commercial solutions; hence, as an advantage, excessive
venous catheter-related infection developed by our group, manipulation of the preparation is avoided. On the other hand,

528
Antibiotic-lock for S. aureus infection
although there is a potential risk of nephrotoxicity in humans
secondary to flushing of gentamicin into the bloodstream, this
risk is almost negligible in experienced centres with trained
personnel.
There is little published experience about conservative man-
agement of S. aureus CRB in humans because most studies
exclude these cases based on a high rate of failures (up to
59%), as was explained above.3 However, although it is well
recognized that the safest option for these patients is to
remove the catheter, this measure is not always possible. To
date, vancomycin is the antimicrobial most widely reported in
the literature for treating long-term S. aureus CRB by ALT.1 – 3,8
Based on our results, the use of gentamicin for this purpose
would result in a fast decrease in S. aureus cfu counts, almost
sterilizing the catheter in 24 h, and could be a safer treatment
than the currently used vancomycin.
This study has several limitations. First of all, different concen-
trations of antimicrobials were used and thus the possibility that
the higher activity of gentamicin could be due to the higher con-
centration used cannot be ruled out. Secondly, although combi-
nation of antimicrobials and anticoagulants is performed in the
clinical setting, we did not do it with the aim of establishing
the antimicrobial effectiveness without the influence of other
substances. Moreover, the use of heparin has been associated
with stimulation of biofilm formation in S. aureus infections.23
Nevertheless, further experimental studies evaluating the combi-
nation of several antimicrobials and anticoagulants for treating
S. aureus CRB by means of the ALT are warranted. Finally,
antibiotic-lock was only allowed to continue in the catheter for
24 h. In S. aureus infections, due to its virulence, it is crucial to
start an aggressive and effective treatment as soon as possible.
Thus, although data about .24 h of ALT would be very interest-
ing (and therefore warranted), the most important aim is to
achieve the sterilization of the catheter during the first few
hours in order to avoid further complications.
In conclusion, gentamicin showed the highest activity against
both MSSA and MRSA biofilms, vancomycin and linezolid showed
no activity or little activity, and ciprofloxacin was more effective
than vancomycin and linezolid in one of the MSSA strains. More
studies are needed to investigate whether these findings can
be extended to other Gram-positive microorganisms, particularly
coagulase-negative Staphylococcus infections. In addition, in the
light of these results, gentamicin use could be contemplated for
the small number of patients with S. aureus catheter infection in
whom the catheter should be maintained in place and the
antibiotic-lock technique used.
Acknowledgements
We thank Celine Cavallo for English language assistance. We thank
Leonor Pou for immunofluorescence assays.
Funding
This work was supported by a research grant from Pfizer España, S.A., and
by a grant from the Fondo de Investigaciones Sanitarias (FIS exp. No. 07/
0347).
JAC
Transparency declarations
N. F.-H., J. G., B. A., M. T. M. and A. P. belong to the Spanish Network for
Research in Infectious Diseases (REIPI RD 06/2008). Other authors:
none to declare.
References
Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020
1 Fernández-Hidalgo N, Almirante B, Calleja R et al. Antibiotic-lock
therapy for long-term intravascular catheter-related bacteraemia:
results of an open, non-comparative study. J Antimicrob Chemother
2006; 57: 1172– 80.
2 Poole CV, Carlton D, Bimbo L et al. Treatment of catheter-related
bacteraemia with an antibiotic lock protocol: effect of bacterial
pathogen. Nephrol Dial Transplant 2004; 19: 1237 –44.
3 Maya ID, Carlton D, Estrada E et al. Treatment of dialysis
catheter-related Staphylococcus aureus bacteremia with antibiotic lock:
a quality improvement report. Am J Kidney Dis 2007; 50: 289–95.
4 Dugdale DC, Ramsey PG. Staphylococcus aureus bacteraemia in
patients with Hickman catheters. Am J Med 1990; 89: 137– 41.
5 Mermel LA, Farr BM, Sherertz RJ et al. Guidelines for the management
of intravascular catheter-related infections. Clin Infect Dis 2001; 32:
1249– 72.
6 Capdevila JA, Gavaldà J, Fortea J et al. Lack of antimicrobial activity of
sodium heparin for treating experimental catheter-related infection due
to Staphylococcus aureus using the antibiotic-lock technique. Clin
Microbiol Infect 2001; 7: 206– 12.
7 Giacometti A, Cirioni O, Ghiselli R et al. Comparative efficacies of
quinupristin-dalfopristin, linezolid, vancomycin, and ciprofloxacin in
treatment, using the antibiotic-lock technique, of experimental
catheter-related infection due to Staphylococcus aureus. Antimicrob
Agents Chemother 2005; 49: 4042 –5.
8 Fortún J, Grill F, Martı́n-Dávila P et al. Treatment of long-term
intravascular catheter-related bacteraemia with antibiotic-lock therapy.
J Antimicrob Chemother 2006; 58: 816–21.
9 Gudiol F, Aguado JM, Pascual A et al. [Consensus document
for the treatment of bacteremia and endocarditis by methicillin-
resistant Staphylococcus aureus]. Enferm Infecc Microbiol Clin 2009; 27:
105–15.
10 Bailey E, Berry N, Cheesbrough JS. Antimicrobial lock therapy for
catheter-related bacteraemia among patients on maintenance
haemodialysis. J Antimicrob Chemother 2002; 50: 615– 7.
11 Benoit JL, Carandang G, Sitrin M et al. Intraluminal antibiotic
treatment for central venous catheter infections in patients receiving
parenteral nutrition at home. Clin Infect Dis 1995; 21: 1286 –8.
12 Krishnasami Z, Carlton D, Bimbo L et al. Management of hemodialysis
catheter-related bacteremia with an adjunctive antibiotic lock solution.
Kidney Int 2002; 61: 1136– 42.
13 Anhalt JP. Antimicrobial assays. In: Washington JA, ed. Laboratory
Procedures in Clinical Microbiology. New York: Springer-Verlag, 1985;
691–729.
14 Clinical and Laboratory Standards Institute. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically:
Approved Standard M7-A8. CLSI, Wayne, PA, USA, 2009.
15 Kagamata-Kiyoura Y, Abe S, Yamaguchi H et al. Detachment activity
of human saliva in vitro for Candida albicans cells attached to a plastic
plate. J Infect Chemother 2003; 9: 215–20.
529
Fernández-Hidalgo et al.
16 Clinical and Laboratory Standards Institute. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically:
Approved Standard M7-A7. CLSI, Wayne, PA, USA, 2006.
17 Ghiselli R, Giacometti A, Cirioni O et al. Pretreatment with the
protegrin IB-367 affects Gram-positive biofilm and enhances
the therapeutic efficacy of linezolid in animal models of central
venous catheter infection. JPEN J Parenter Enteral Nutr 2007; 31:
463–8.
18 Cirioni O, Giacometti A, Ghiselli R et al. RNAIII-inhibiting
peptide significantly reduces bacterial load and enhances the
effect of antibiotics in the treatment of central venous
catheter-associated Staphylococcus aureus infections. J Infect Dis 2006;
193: 180–6.
530
19 Ceri H, Olson ME, Stremick C et al. The Calgary biofilm device: new
technology for rapid determination of antibiotic susceptibilities of
bacterial biofilms. J Clin Microbiol 1999; 37: 1771– 6.
20 Bookstaver PB, Williamson JC, Tucker BK et al. Activity of novel
antibiotic lock solutions in a model against isolates of catheter-related
bloodstream infections. Ann Pharmacother 2009; 43: 210–9.
21 Jefferson KK, Goldmann DA, Pier GB. Use of confocal microscopy
to analyze the rate of vancomycin penetration through Staphylococcus
aureus biofilms. Antimicrob Agents Chemother 2005; 49: 2467– 73.
22 Costerton JW, Stewart PS, Greengerg EP. Bacterial biofilms: a common
cause of persistent infections. Science 1999; 284: 1318– 22.
Downloaded from https://academic.oup.com/jac/article-abstract/65/3/525/748938 by guest on 13 February 2020
23 Shanks RMQ, Donegan NP, Graber ML et al. Heparin stimulates
Staphylococcus aureus biofilm formation. Infect Immun 2005; 73: 4596–606.