|Year : 2012 | Volume
| Issue : 4 | Page : 743-754
|Cefotaxime-heparin lock prophylaxis against hemodialysis catheter-related sepsis among Staphylococcus aureus nasal carriers
Anil K Saxena1, Bodh R Panhotra2, Abdul Aziz Al-hafiz3, Dasappan S Sundaram3, Bassam Abu-Oyun3, Khalifa Al Mulhim4
1 Nephrology Division, Al-Rahba Hospital-Johns Hopkins Medicine International, Abu Dhabi, United Arab Emirates
2 Department of Microbiology, King Fahad Hospital and Tertiary Care Center, Hofuf, Al-Hassa, Eastern Province, Kingdom of Saudi Arabia
3 Nephrology Division, King Fahad Hospital and Tertiary Care Center, Hofuf, Al-Hassa, Eastern Province, Kingdom of Saudi Arabia
4 Department of Family Medicine, King Fahad Hospital and Tertiary Care Center, Hofuf, Al-Hassa, Eastern Province, Kingdom of Saudi Arabia
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|Date of Web Publication||9-Jul-2012|
| Abstract|| |
Staphylococcus aureus nasal carriers undergoing hemodialysis (HD) through tunneled cuffed catheters (TCCs) form a high-risk group for the development of catheter-related bloodstream infections (CRBSI) and ensuing morbidity. The efficacy of antibiotic-locks on the outcomes of TCCs among S. aureus nasal carriers has not been studied earlier. Persistent nasal carriage was defined by two or more positive cultures for methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) S. aureus of five standardized nasal swabs taken from all the participants dialyzed at a large out-patient HD center affiliated to a tertiary care hospital. Of 218 participants, 82 S. aureus nasal carriers dialyzed through TCCs (n = 88) were identified through April 2005 to March 2006 and randomized to two groups. Group I comprised of 39 nasal carriers who had TCCs (n = 41) "locked" with cefotaxime/heparin while group II included 43 patients with TCCs (n = 47) filled with standard heparin. The CRBSI incidence and TCC survival at 365 days were statistically compared between the two groups. A significantly lower CRBSI incidence (1.47 vs. 3.44/1000 catheter-days, P <0.001) and higher infection-free TCC survival rates at 365 days (80.5 vs. 40.4%, P <0.0001) were observed in the cefotaxime group compared with the standard heparin group. However, no significant difference in MRSA-associated CRBSI incidence was observed between the two groups. Cefotaxime-heparin "locks" effectively reduced CRBSI-incidence associated with gram-positive cocci, including MSSA, among S. aureus nasal carriers. There remains a compelling requirement for antibiotic-locks effective against MRSA.
|How to cite this article:|
Saxena AK, Panhotra BR, Al-hafiz AA, Sundaram DS, Abu-Oyun B, Al Mulhim K. Cefotaxime-heparin lock prophylaxis against hemodialysis catheter-related sepsis among Staphylococcus aureus nasal carriers. Saudi J Kidney Dis Transpl 2012;23:743-54
|How to cite this URL:|
Saxena AK, Panhotra BR, Al-hafiz AA, Sundaram DS, Abu-Oyun B, Al Mulhim K. Cefotaxime-heparin lock prophylaxis against hemodialysis catheter-related sepsis among Staphylococcus aureus nasal carriers. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Sep 21];23:743-54. Available from: http://www.sjkdt.org/text.asp?2012/23/4/743/98154
| Introduction|| |
Catheter-related blood stream infections (CRBSIs) continue to be an important cause of morbidity and mortality among hemodialysis (HD) patients as nearly 60% of incident and 17% of prevalent end-stage renal disease (ESRD) patients in the United States and 31% of incident and 8% of prevalent ESRD patients in Europe continue to depend upon tunneled cuffed catheters (TCCs) for access to the blood circulation for the commencement and/or maintenance of long-term HD.  Although the majority of the CRBSI episodes are caused by Gram positive organisms, S. aureus-related infections are often associated with metastatic complications with most devastating clinical consequences and increased cost of ESRD management. 
Nasal carriage of S. aureus is a recognized risk factor for the development of CRBSIs of endogenous origin. ,, The Vestibulum nasi are the main ecological niche where the organisms colonize and then disseminate to the other parts of the body. , The bacterial colonization of HD catheters occurs more frequently due to luminal contamination than the migration of bacteria from the skin through the catheter exit site.  Von Eiff et al reported that S. aureus isolated from blood samples of septicemic patients were clonally identical to those obtained from nasal specimens in 82.2% patients, signifying that the organisms in the bloodstream originated from the individual's own nasal flora.  Repeated CRBSI episodes reduce the lifespan of TCCs and increase patient mortality. ,
Several recent randomized clinical trials have demonstrated the efficacy of antimicrobial- anticoagulant "lock" solutions in the prevention of CRBSI and enhancement of the lifespan of HD catheters besides significant reduction in CRBSI-associated patient mortality. ,, Nonetheless, the efficacy of intraluminal antibiotic "locks" in the prevention of CRBSI in the particularly vulnerable group of S. aureus nasal carriers has not been investigated earlier.
| Subjects and Methods|| |
This prospective cohort study was carried out at a large out-patients dialysis facility affiliated to the King Fahad Hospital and Tertiary Care Center of Eastern Province of Kingdom of Saudi Arabia to evaluate the efficacy of intra-luminally instilled cefotaxime/heparin "lock" against the regular practice of filling of TCCs with standard heparin (i.e., 5000 IU/mL of unfractionated heparin) in the prevention of CRBSI and ensuing mortality among the ESRD patients with S. aureus nasal carriage. The selection of cefotaxime for intraluminal placement was based upon its broad-spectrum, proven clinical and microbiological efficacy and safety record among critically ill patients and the complete lack of ototoxic potential. ,
All the S. aureus nasal carriers aged 18 years or more requiring TCC placement for the maintenance or initiation of HD between April 2005 and March 2006 were eligible for the study. Patients were required to sign the informed consent document with the obligatory adherence to the "lock" protocol and HD-treatment schedule. Patients having reinsertion of a TCC through a new access-site were also included in the study.
Patients who had active sepsis received prolonged (more than seven days) antibiotic therapy; patients with known hypersensitivity to heparin or cephalosporins and those who had TCC exchanged over guidewire through the same exit-site were excluded from the study. Patients with existing exit-site or catheter tunnel infection and the pregnant women with ESRD were also excluded from the study.
Randomization plan and study population
Sealed, opaque envelopes, numbered in sequence were used for randomization, with the sequence of interventions being obtained from a computer-generated random number list to ensure the concealment of the patient's assignment to the specific treatment group. The investigators, coordinators, patients and all the members of the research team, including microbiologists and HD staff, were blinded to the treatment allocation. The pharmacy dispensed equal number of identical syringes filled with either cefotaxime/heparin or heparin alone to maintain blinding. For the patients on the group I, syringes contained cefotaxime/heparin (cefotaxime, 10 mg/mL and heparin, 5000 IU/mL), and for the group II, all the syringes were filled with standard heparin 5000 IU/mL, numbered according to the order of instillation. The volumes of each of these locking solutions were equal to the catheter-luminal volume. All the syringes were coded and labeled by a central pharmacy.
Of the total (n = 104) TCCs insertions in 99 nasal carriers identified among 218 ESRD patients enrolled during study period, 85 patients with TCCs (n = 91) consented and were randomized to two groups: 40 patients with TCCs (n = 42) to group I with cefotaxime- heparin lock and 45 patients with TCCs (n = 49) to group II having filled with standard heparin (5000 IU/mL). One patient from group I was excluded as he violated the protocol and two patients from group II were excluded because they were on antibiotics for prolonged periods for different reasons, leaving 39 patients with TCCs (n = 41) in group I and 43 patients with TCCs (n = 47) in group II, eventually [Figure 1].
Patients were dialyzed three-times per week for 3-4 h through a double-lumen cuffed Perm-cath® (Quinton Instrument Co. Seattle, WA, USA) placed by experienced vascular surgeons under fluoroscopic screening in the dedicated operation rooms with stringent adherence to aseptic technique. Proper positioning of TCCs was confirmed by chest radiographs taken after catheter placement. No pre-operative antibiotic prophylaxis was used nor were the patients given any nasal decolonizing agent topical or oral. The demographic profile, clinical characteristics and reasons for the TCCs insertion in the patients of each group are shown in [Table 1] and [Table 2], respectively.
|Table 1: Clinical characteristics and demographic profile of ESRD patients with S. aureus nasal carriage in group I (cefotaxime/heparin locked) and group II (heparin alone).|
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|Table 2: Reasons of TCC insertion in group I (cefotaxime/heparin "locked") and group II (heparin alone).|
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Screening for the S. aureus nasal carriage
The procedure for optimal screening of nasal carriage of S. aureus among patients on HD use was performed by using three cultures at intervals of 1 h on Day one and culture four and five were taken at subsequent dialysis sessions, with each interdialysis interval spanning no less than 48 h.  A cotton swab moistened in sterile 0.9% NaCl solution was rotated in both the anterior nares and placed into modified amines charcoal transport medium (Eurotuba, Barcelona, Spain). These swabs were processed in the laboratory within 12 h. Patients who were culture positive for S. aureus on more than two occasions were labelled as persistent nasal carriers for S. aureus. The nasal swabs were cultured on blood agar and mannitol salt agar for methicillin susceptible S. aureus (MSSA) and mannitol salt agar supplemented with 6 μg/mL of oxacillin for methicillin resistant S. aureus (MRSA). The culture plates were incubated at 35°C for 48 h. The S. aureus was identified on the basis of colony morphology (golden pigmentation of colonies), Gram-positive cocci in clusters on microscopic examination and positive results of tube coagulase, Mannitol-fermentation, deoxyribonuclease (DNAse) and Staphaurex latex-agglutination tests (Murex Bio Tech, Dartford, UK).
Thus, five standardized swabs were taken from the anterior nares of all the patients on longterm HD. Persistent nasal carriage was defined by two or more positive cultures for MSSA or MRSA.
"Lock" preparation and placement
Antibiotic lock solutions were freshly prepared at the HD out patients' pharmacy by the qualified pharmacists on a daily basis by directly dissolving Cefotaxime sodium (Claforan, Hoechst Roussel, NJ, USA) powder in unfractioned he-parin (heparin sodium, Unihep® , Leo Pharma-ceuticals, NJ, USA) under sterile conditions to obtain a final concentration of 10 mg/mL for cefotaxime and 5000 units/mL for heparin in the "lock" solution. Each lock volume of approximately 2.5 mL contained 25 mg of cefotaxime and 12,500 units of heparin to fill 1.3 mL of venous and 1.2 mL of arterial lumina of TCC at the end of each HD session in group I patients. For preventing accidental exit of the locking solution into the circulation during the placement, syringes of maximum 2.5 mL size were used. The "locks" were removed at the beginning of each HD by sterile syringe to avoid systemic spill-out of antibiotic during the procedure and placed again at the completion of HD to stay intraluminally during the inter-dialytic period. The development of symptomatic CRBSI and 365 days TCC survival were the primary endpoints, while the events that led to elective removal of the catheter and CRBSI-related death were used to censor the TCCs follow-up.
CRBSI diagnosis and related definitions
CRBSI was diagnosed using clinical and microbiological criteria as defined by the Centers for Disease Control (CDC).  CRBSI was considered when the same organism (i.e., identical species, antibiogram) was isolated from a quantitative culture of the distal segment of catheter and from the blood of a patient with accompanying clinical signs of sepsis and no other apparent source of infection.
Suspected cases of CRBSI were treated for two weeks with an empirical regimen comprising of intravenous vancomycin and an amino-glycoside given post-dialysis; this regimen was modified at the earliest availability of blood culture results. Pre-dialysis plasma levels of aminoglycosides were monitored regularly. Catheters were only removed if sepsis persisted (failure to render patient apyrexial within 48 h) despite initiation of antibiotic therapy. Further, CRBSI episodes were only categorized as new infections if they occurred no less than two weeks after the cessation of initial successful antibiotic therapy. ,
CRBSI-related mortality was defined as death of a patient with clinical signs of sepsis with no other obvious source of infection and the isolation of the same organism from a quantitative blood culture from the catheter and the peripheral blood.
A catheter exit-site infection was defined as a positive (semi-) quantitative culture of the drainage material with local signs of inflammation.
Exit sites were dressed with Opsite (Smith and Nephew, Hull, England) and kept under supervision at each HD treatment session.
| Statistical Analysis|| |
A sample size of 90 TCCs (45 in each group) calculated to be of power to detect 30% difference in the two treatments at a one-sided 0.05 level of significance was based on the previous experience of baseline risk of 2.2 CRBSI episodes/1000 catheter-days at this tertiary care center. 
The SPSS, version 10.1, Chicago, IL, USA, was used for data processing. The Chi-square test was used to assess the difference among CRBSI incidence and infection-free catheter-survival between the two groups. The Student t-test was used to compare between the means of two quantitative variables.
The Kaplan Meier method was used to obtain the cumulative survival curves. The prognostic significance of CRBSI incidence on the percent survival of TCCs in relation to duration of catheterization was tested at the main time points (the time of HD catheter-infection and/ or removal from the time of catheter placement). The differences in the cumulative survival curves were assessed by the Log-rank test.
| Results|| |
Screening of 218 ESRD patients undergoing maintenance HD finally identified 82 (37.6%) S. aureus nasal carriers (69 MSSA and 13 MRSA) with TCCs (n = 88). They were randomized to two treatment groups.
The mean age (±SD) of 53.7 ± 17.2 (range, 34-89 years) in the nasal carriers randomized to the cefotaxime group (group I) was comparable to that of 51.9 ± 19.1 (range, 32-82 years) in the heparin-alone group (group II). The male/ female ratio and the proportions of the elderly/diabetics, hematocrit, serum iron/ ferritin, serum albumin, glycosylated hemoglobin (HbA1c) levels and adequacy of HD (Kt/V) that could alter the risk of CRBSI were also comparable between the two groups [Table 1].
Overall, 88 TCCs placed among 82 nasal carriers recorded 80 episodes of CRBSI in 32,120 catheter-days (2.49/1000 catheter-days), with mean percent catheter-survival at 365 days of 59.1% (52/88) and CRBSI-related mortality of 15.8% (13/82) during the study period.
Patients with cefotaxime-heparin lock (group I) had higher infection-free TCC survival at 365 days (80.5 vs. 40.4%, OR-6.065, 95% CI, 3.074-12.065, P <0.0001) besides having significantly lower CRBSI rate (1.47 vs. 3.44 episodes/1000 catheter-days, OR-0.144, 95% CI, 0.067-0.304, P <0.001) and CRBSI-related mortality (10.2 vs. 20.9%, OR-0.430, 95% CI, 0.177-1025, P <0.05) compared with those on heparin alone (group II).
There was a significant reduction in the CRBSI incidence caused by gram positive cocci (1.00 vs. 1.63 episodes/1000 catheter days, OR-0.429, 95% CI, 0.195-0.936, P = 0.032) including MSSA (OR-0.383, 95% CI, 0.141-1.012, P <0.05) and gram negative bacilli (OR-0.159, 95% CI, 0.065-0.375, P <0.0001) in the cefotaxime/heparin-locked group against that of heparin alone.
However, no significant difference in the MRSA-associated CRBSI incidence (OR-0.740, 95% CI, 0.127-4.079, P = 1.000) was observed between the two groups [Figure 2], [Table 3].
|Figure 2. Kaplan Meier cumulative survival curves demonstrating the probability of TCC survival at 365 days in groups I and II.|
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|Table 3: Catheter-events among ESRD patients with S. aureus nasal carriage in group I (cefotaxime/heparin "locked") and group II (heparin alone).|
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| Discussion|| |
S. aureus thrives on the nasal mucosa apparently in the relative lack of human immunological defences among the ESRD patients mostly with advanced age and type 2 diabetes mellitus. ,, Dialysis-dependent ESRD patients with S. aureus nasal carriage characterize a high-risk group for the development of CRBSI and resultant serious systemic complications. ,
The policy of optimizing arteriovenous fistula (AVF) prevalence and reducing reliance on the venous catheters as dialysis access remains a golden guideline to effectively reduce the CRBSI incidence among ESRD patients, regardless of the S. aureus nasal carriage.  However, other strategies having potentials to lessen CRBSI incidence in this vulnerable group include deployment of oral/topical nasal decolonizing agents, topical application of mupirocin ointment at the dialysis catheter-exit site, use of antistaphylococcal vaccine and intraluminal placement of antimicrobial-anticoagulant "lock" solutions.
Yu et al, in their five-year prospective study, reported significant reduction in S. aureus carriage over a one-month follow-up period among HD patients who received oral rifampicin for five days. However, rifampicin prophylaxis led to emergence of resistant strains of S. aureus isolated from the nostrils of four participants.  Boelaert et al reported a four-fold reduction in the incidence of S. aureus bacteremia with mupirocin use (0.024 vs. 0.097 per patient-year, P = 0.008) following nasal decolonization among 96.3% of ESRD patients. 
Johnson et al, in their open-label trial, observed a significant reduction in CRBSI (7 vs. 35%, P <0.01) and higher median catheter-survival (108 vs. 31 days, P <0.05) in the patient-group treated with thrice-weekly application of mupirocin to catheter exit-sites against those with no ointment application. 
However, efforts to realize the long-term elimination of S. aureus from the anterior nares through decolonizing agents such as oral rifampicin and mupirocin nasal applications have been associated with the development of unnecessary side-effects (of rifampicin), reduced effectiveness of drug in the long-term, emergence of resistance and recolonization of S. aureus once the drug was discontinued. 
Alternatively, proposed use of a conjugate vaccine confers only partial immunity against S. aureus bacteremia for approximately 40 weeks in patients receiving HD, after which protection wanes as antibody levels begin to decline. 
Majority of the HD catheters become colonized with bacteria embedded in a biofilm within 24 h of insertion. Biofilms protect invading bacteria and facilitate their multiplication and dissemination into the blood-stream.  Instillation of an antimicrobial-anti-coagulant combination as "lock" solution promptly after the catheter placement creates an intraluminal environment intimidating to potentially infecting microorganisms. ,,
Several well-designed, controlled, prospective trials using an array of antimicrobials (non-antibiotic/antibiotic) as "lock" solutions have shown significant reduction in CRBSI incidence and ensuing mortality among high-risk HD patients; however, no trial has exclusively examined ESRD patients with S. aureus nasal carriage.
Allon reported significantly higher bacteremia-free TCC survival at 90 days (94% vs. 47%; P <0.001) among patients who received taurolidine-citrate locks than among patients who received only heparin.  Betjes et al, in their single-center trial involving 76 central venous catheters (CVCs) placed among 58 patients, observed four CRBSI episodes in the heparin group versus none (P <0.5) in the patients with CVCs locked with 1.35% taurolidine and 4% sodium citrate.  However, there was an increased requirement for thrombolytic interventions to maintain catheter-patency among patients who received taurolidine-citrate locks than those in the control group (32% vs. 76%; P <0.001).  Catheter patency problems were in fact attributed to the protein denaturation that occurs from aldehyde produced by metabolism of taurolidine. Geron et al suggested addition of heparin to the "Tauro-Lock T" solution to maintain catheter patency. 
Weijmer et al, in their multicenter trial, also observed reduced CRBSI (87%, P <0.001) and higher catheter patency rates (P = 0.005) among patients with TCCs locked with 30% trisodium citrate (TSC) plus heparin as compared to those locked with heparin alone.  TSC provides a local anticoagulant and antimicrobial effect apparently by chelation and removal of calcium ions from the surrounding milieu. Accordingly, transient dizziness, perioral/peri-pheral paresthesias and metallic taste were the most common side-effects observed in this study.
However, Power et al (2009), in their singlecenter randomized controlled trial involving ESRD patients (n = 232) with TCCs, observed no significant difference in CRBSI incidence (0.7 vs. 0.7/1000 catheter-days) between the treatment groups using TSC (46.7%) and control group with standard heparin, creating controversy over the effectiveness of the TSC "lock" in the prevention of CRBSI. 
Moreover, prolongation of QT interval leading to torsade de pointes and subsequent death has been reported following inadvertent rapid push of TSC through TCC. ,
Among the randomized controlled trials on antibiotic locks, gentamicin was the most frequently used antibiotic in combination with heparin/citrate. Cooper et al (1999) pioneered a trial using gentamicin/citrate combination (40 mg/mL, 3.13% TSC, respectively) in the prevention of bacteremia among ESRD patients (n = 36) with TCCs. Remarkable reduction in the CRBSI incidence in the intervention group compared versus the control group (0 vs. 3.11/1000 catheter-day) was observed. 
Later, Pervez et al (2002) observed a spectacular decline in CRBSI (0.62 vs. 2.11/1000 patient-days) and enhanced percent catheter-survival at 60 days (74.0 ± 12 vs. 59.0 ± 11, P = 0.03) in the gentamicin-citrate "locked" (40 mg/mL plus 4.6% TSC) group compared with those locked with standard heparin.  Dogra et al (2002) reaffirmed the findings of earlier investigators with a significant reduction in CRBSI incidence (P = 0.003) and greater infection-free catheter survival rates (282 days vs. 181 days, P = 0.002) in the gentamicin/TSC (40 mg/mL and 3.13%, respectively) group versus the heparin group. However, authors observed higher pre-dialysis gentamicin levels among the subjects randomized to the gentamicin group (2.8 mg/L vs. <0.2 mg/L, P = 0.008) and ototoxic symptoms in about 10% of the patients, raising the safety concerns of the "locked" dose of gentamicin for ototoxicity. 
McIntyre et al (2004) used a lower dose of gentamicin (5 mg/mL) in combination with standard heparin (5000 IU/mL), yet demonstrated a significant reduction in CRBSI incidence against the heparin-alone group (0.3/1000 catheter days vs. 4/1000 catheter days, P = 0.02).  No symptoms suggestive of ototoxicity were observed, while measured pre-dialysis plasma gentamicin levels remained low (<0.2 mg/L).
Similar findings in subsequent trials virtually established the efficacy of low-dose gentamicin "locks" in the prevention of CRBSI among ESRD patients with tunneled/untunneled catheters. ,,, Nonetheless, irreversible ototoxicity has been reported even with the lower "lock" concentration of aminoglycosides due to slow accumulation of "spilled-over" drug in the cochlear fluid up to the ototoxic threshold level over prolonged periods. , Moreover, emergence of microbial resistance to gentamicin had been reported in recent studies from France and New Zealand. ,
Thus, the odds of ototoxicity and emergence of microbial resistance, besides the likelihood of decline in residual renal function with the use of gentamicin "locks", cardiotoxicity and catheter-patency problems with the use of TSC and taurolidine/citrate "lock" solutions, respectively, raise safety concerns about presently available catheter-lock solutions. The choice of cefotaxime over other antimicrobials, in the present study, was primarily based on the lack of cardio/ototoxic potentials of the basic components of this TCCs "locking" solution besides its broad spectrum microbial coverage. , The excellent clinical efficacy and safety profile of cefotaxime/heparin locking solution has been established in earlier trials conducted among type 2 diabetics and the elderly ESRD patients in the prevention of CRBSI. ,,
The prevalence of S. aureus nasal carriage of 37.6% (MSSA-31.6% and MRSA-5.9%) observed in our study was lower than that of 44- 55% (MSSA 41% and MRSA 12%) reported elsewhere. ,, An overall CRBSI incidence of 2.49/1000 catheter-days with mean percent TCC-survival at 365 days of 59.1% (52/88) and CRBSI-related mortality of 15.8% (13/82) were observed in the present study.
Cefotaxime/heparin lock placement among ESRD patients with S. aureus nasal carriage led to significant overall reduction in the CRBSI incidence (1.47 vs. 3.44 episodes/1000 catheter-days, P <0.001) and CRBSI associated mortality (10.2 vs. 20.9%, P <0.05) compared with heparin alone. The "lock" was found to be more effective against gram-positive cocci (P = 0.032), including MSSA (P <0.05) and gram negative bacilli (P <0.0001). However, the cefotaxime lock provided no protection against MRSA-associated CRBSIs [Table 3]. However, this trial was powered to have 45 TCCs in each group, and yet group I, the intervention arm, had 41 TCCs. This could have had an effect in under-powering and potentially affecting the strength of results.
The difference between MRSA and MSSA is the resistance to β-lactamase-stable β-lactam antibiotics. The MRSA nasal carriage constitutes a greater risk for the development of S. aureus infection than does MSSA carriage. This could be related to the resistance itself, elevated intrinsic virulence of MRSA versus MSSA or increased vulnerability of the hosts being colonized by MRSA, for instance ESRD patients with type 2 diabetes mellitus and advanced age.  Analysis of Kaplan Meier survival curves revealed significantly higher infection-free TCC survival at 365 days (log rank P = 0.002) in the cefotaxime-heparin locked group compared with that of heparin alone. While the overall CRBSI and related mortality rates observed in the present study were lower than those reported elsewhere among high-risk groups, the percent catheter-survival rates were either comparable or relatively higher than those published in recent randomized trials. ,,,,,,,,,,,,
No emergence of resistance to cefotaxime was observed among the bacterial strains isolated from CRBSI episodes occurring during 365 days of the study period, conceivably owing to the existence of >100-folds concentration of drug with respect to MIC in the "locks" that were applied promptly after TCC placement to prevent bacterial biofilm formation. However, no adverse reactions what-so-ever to the components of lock solution were observed during the study period.
Thus, catheter-restricted filling of cefotaxime/ heparin during the interdialytic period is a safe and effective approach to prevent CRBSI and associated mortality among ESRD patients with S. aureus nasal carriage. There remains a compelling need for an appropriate antibiotic-lock to prevent MRSA-associated CRBSIs among S. aureus nasal carriers. The potential benefits of the technique must be cautiously weighed against the imminent risk of emergence of antimicrobial resistance associated with the long-term use of intraluminal antibiotics.
| Acknowledgments|| |
The authors gratefully acknowledge the invaluable help and the earnest support rendered by Mr. Saleh Al-Quaimi, Director Manager of Al-Jabr Kidney Center, King Fahad Hospital and Tertiary Care Center, King Faisal University, Eastern Province of Saudi Arabia.
| References|| |
|1.||Pisoni RL, Young EW, Dykstra DM, et al. Vascular access use in Europe and the United States: results from the DOPPS. Kidney Int 2002;61:305-16 |
|2.||Yanhong LI, Friedman JY, O'Neal BF, et al. Outcomes of Staphylococcus aureus infection in hemodialysis-dependent patients. Clin J Am Soc Nephrol 2009;4:428-34. |
|3.||Saxena AK, Panhotra BR, Uzzaman W, Venkateshappa CK. The role of staphylococcus aureus nasal carriage and type of vascular access in the outcome of high-risk patients on hemodialysis. J Vasc Access 2002;3:74-9. |
|4.||Kaplowitz LG, Comstock JA, Landwehr DM, Dalton HP, Mayhall CG. Prospective study of microbial colonization of nose and skin and infection of vascular access site in haemodialysis patients. J Clin Microbiol 1988;26:1257-62. |
|5.||Von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. N Engl J Med 2001;344:11-6. |
|6.||Feely T, Copley A, Bleyer AJ. Catheter - lock solutions to prevent bloodstream infections in high-risk hemodialysis patients. Am J Nephrol 2007;27:24-9. |
|7.||Yahav D, Rozen-Zvi B, Gafter-Gvili A, Leibovici L, Gafter U, Paul M. Antimicrobial lock solutions for the prevention of infections associated with intravascular catheters in patients undergoing hemodialysis: Systematic review and meta-analysis of randomized, controlled trials. Clin Infect Dis 2008;47:83-93. |
|8.||Rabindranath KS, Bansal T, Adams J, et al. Systematic review of antimicrobials for the prevention of hemodialysis catheter-related infections. Nephrol Dial Transplant 2009;24 (12):3763-74. |
|9.||Francisco IL, Mercedes P, Pedro O, Rafel S, Enrique C. Cefotaxime, twenty years later; Observational study in critically ill patients. Enferm Infecc Microbiol Clin 2001;19:211-8. |
|10.||Saxena AK, Panhotra BR. Locking hemodialysis catheters with cefotaxime instead of gentamicin to avoid ototoxicity. Kidney Int 2005;67:2505-6. |
|11.||Geert JA, Peter MS, Annielies B, Egidia VG, Marrianne IK. Optimizing screening procedures for Staphylococcus aureus nasal carriage in patients on haemodialysis. Nephrol Dial Transplant 1998;13:1256-58. |
|12.||Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections. Am J Infect Control 1988;16:128-40. |
|13.||Saxena AK, Panhotra BR. Haemodialysis catheter-related bloodstream infections: current treatment options and strategies for prevention. Swiss Med Wkly 2005;135:127-38. |
|14.||Raad II, Sabbagh MF. Optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia: a study of 55 cases and review. Clin Infect Dis 1992 14:75-82. |
|15.||Koziol-Montewka M, Chudnicka A, Ksiazek A, Majdan M. Rate of Staphylococcus aureus nasal carriage in immunocompromised patients receiving haemodialysis treatment. Int J Antimicrob Agents 2001;18:193-6. |
|16.||Saxena AK, Panhotra BR, Chopra R. Advancing age and the risk of nasal carriage of Staphylococcus aureus, among patients on long-term hospital-based hemodialysis. Ann Saudi Med 2004;24:337-42. |
|17.||Saxena AK, Panhotra BR, Venkateshappa CK, et al. The impact of nasal carriage of methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA & MSSA) on vascular access-related septicemia among patients with type-II diabetes on dialysis. Ren Fail 2002;24:763-77. |
|18.||Hoen B. Infective endocarditis: a frequent disease in dialysis patients Nephrol Dial Transplant 2004;19:1360-2. |
|19.||Saxena AK, Panhotra BR, Naguib Mohammed FM, et al. The impact of achieving the target goal for AV fistulas, as set by NKF-DOQI, on Staphylococcus aureus septicemia. Nephrol Dial Transplant 2002;31:16-23. |
|20.||Yu VL, Goetz A, Wagener M. Staphylococcus aureus carriage and infection in patients on haemodialysis, efficacy of antibiotic prophylaxis. N Engl J Med 1986;315:91-6. |
|21.||Boelaert JR, De Smedt RA, De Baere YA, et al. Nasal mupirocin ointment decreases the incidence of Staphylococcus aureus bacteremia in hemodialysis patients. Nephrol Dial Transplant 1989;4:278-81. |
|22.||Johnson DW, Mac Ginley R, Kay TD, et al. A randomized controlled trial of topical exit site mupirocin application in patients with tunneled, cuffed hemodialysis catheters. Nephrol Dial Transplant 2002;17:1802-7. |
|23.||Watanabe H, Masaki H, Asoh N, Watanabe K, Oishi K, Furumoto A. Emergence and spread of low-level mupirocin resistance in methicillin-resistant Staphylococcus aureus isolated from a community hospital in Japan. J Hosp Infect 2001;47:294-300. |
|24.||Shinefield H, Black S, Fattom A, et al. Use of a Staphylococcus aureus conjugate -vaccine in patients receiving hemodialysis. N Eng J Med 2002;346:491-6. |
|25.||Raad II, Luna M, Khalil SA, Costerton JW, Lam C, Bodey GP. The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 1994;13:1014-6. |
|26.||Mittleman MW, Pelak M, Shah C, Costerton JW. Eradication of microbial biofilms with an antimicrobial catheter-lock solution. General Meeting of American Society of Microbiology, May 2001 (Abstract) |
|27.||Saxena AK, Panhotra BR. Prevention of catheter-related bloodstream infections: An appraisal of developments in designing an infection-resistant 'dream dialysis- catheter'. Nephrology 2005;10:240-8. |
|28.||Allon M. Prophylaxis against dialysis catheter-related bacteremia with a novel antimicrobial-lock solution. Clin Infect Dis 2003;36:1539-44. |
|29.||Betjes MG, Van Agteren M. Prevention of dialysis access-related sepsis with citrate-taurolidine containing lock solution. Nephrol Dial Transplant 2004;19:1546-51. |
|30.||Geron R, Tanchilevski O, Kristal B. Catheters lock solution-taurolock for prevention of catheter-related bacteremia in hemodialysis patients. Harefuah 2006;145:881-4. |
|31.||Weijmer MC, van den Dorpel MA, Van de Ven PJ, et al. CITRATE Study Group. Randomized, clinical trial comparison of trisodium citrate 30% and heparin as catheter-locking solution in hemodialysis patients. J Am Soc Nephrol 2005;16:2769-77. |
|32.||Power A, Duncan N, Singh SK, et al. Sodium citrate versus heparin catheter locks for cuffed central venous catheters: A single-center randomized controlled trial. Am J Kidney Dis 2009;53:1034-41. |
|33.||FDA Issues Warning on Tricitrasol® Dialysis Catheter Anticoagulant. FDA Talk Paper T00-16. 14 - 4, Rockville, MD, US Food and Drug Administration, 2000. |
|34.||Polaschegg HD, Sodemann K. Risks related to catheter locking solutions containing concentrated citrate. Nephrol Dial Transplant 2003; 18:2688-9. |
|35.||Cooper R, Saad T. Prevention of bacteraemia in patients with tunneled cuffed "permanent" hemodialysis catheters (PCs) using gentamicin catheter packing. J Am Soc Nephrol 1999;10: 203A. |
|36.||Pervez A, Ahmad M, Ram S, et al. Antibiotic lock technique for prevention of cuffed tunnel catheter associated with bacteremia. J Vasc Access 2002;3:108-13. |
|37.||Dogra GK, Herson H, Hutchison B, et al. Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling with gentamicin and citrate: a randomized controlled study. J Am Soc Nephrol 2002;13: 2133-9. |
|38.||McIntyre CW, Hulme LJ, Taal M, Fluck RJ. Locking of tunneled hemodialysis catheters with gentamicin and heparin. Kidney Int 2004; 66:801-5. |
|39.||Kim SH, Song KI, Chang JW, et al. Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial. Kidney Int 2006;69:161-4. |
|40.||Nori US, Manoharan A, Yee J, Besarab A. Comparison of low-dose gentamicin with minocycline as catheter-lock solutions in the prevention of catheter-related bacteremia. Am J Kidney Dis 2006;48:596-605. |
|41.||Al-Hwiesh AK, Abdul-Rahman IS. Successful prevention of tunneled, central catheter infection by antibiotic lock therapy using vancomycin and gentamicin. Saudi J Kidney Dis Transpl 2007;18:239-47. |
|42.||Zhang P, Yuan J, Tan H, Lv R, Chen J. Successful prevention of cuffed hemodialysis catheter-related infection using an antibiotic lock technique by strictly catheter-restricted antibiotic lock solution method. Blood Purif 2009;27:206-11. |
|43.||Saxena AK, Panhotra BR, Naguib M. Sudden irreversible sensory-neural hearing loss in a diabetic on hemodialysis, receiving amikacin as antibiotic-heparin lock Pharmacotherapy 2002;22:105-8. |
|44.||Saxena AK. Characteristics of ototoxicity of aminoglycosides "locked" to prevent hemodialysis catheter-related infections. Hemodial Int 2006;10:94. |
|45.||Guerraoui A, Dacosta E, Roche B, et al. Emergence of multiresistant Staphylococcus epidermidis (MRSE) after lock antibiotic regimen by gentamicin in permanent hemodialysis catheters - prospective study (1999 -2003). J Am Soc Nephrol 2004;13:368A. |
|46.||Abbas SA, Haloob IA, Taylor SL, et al. Effect of Antimicrobial locks for tunneled hemodialysis catheters on bloodstream infection and bacterial resistance: a quality improvement report. Am J Kidney Dis 2009; 53(3):492-502. |
|47.||Saxena AK, Panhotra BR, Abdul Aziz H, et al. Tunneled catheter's outcome optimization among diabetics on dialysis through antibiotic lock placement. Kidney Int 2006;70:1629-35. |
|48.||Saxena AK, Panhotra BR. The impact of catheter-restricted filling of Cefotaxime and heparin on the life - span of 'temporary' hemodialysis catheters: a case-controlled study. J Nephrol 2005;18:755-63. |
|49.||Saxena AK, Panhotra BR. Enhancing the survival of tunneled hemodialysis catheters in the elderly: a randomized double-blind clinical trial. Nephrology (Carlton) 2006;11:299-305. |
|50.||Zimakoff J, Bangsgaard Pedersen F, Bergen L, et al. Staphylococcus aureus carriage and infections among patients in four haemo and peritoneal-dialysis centres in Denmark. The Danish Study Group of Peritonitis in Dialysis (DASPID) J Hosp Infect 1996;33:289-300. |
|51.||Peña C, Fernández-Sabe N, Domínguez MA, et al. Staphylococcus aureus nasal carriage in patients on haemodialysis: Role of cutaneous colonization. J Hosp Infect 2004;58:20-7. |
|52.||Lederer SR, Riedelsdorf G, Schiffl H. Nasal carriage of methicillin resistant Staphylococcus aureus: the prevalence, patients at risk and the effect of elimination on outcomes among out clinic haemodialysis patients. Eur J Med Res 2007;12:284-8. |
|53.||Jaar BG, Hermann JA, Furth SL, Briggs W, Powe NR. Septicemia in diabetic hemodialysis patients: comparison of incidence, risk factors, and mortality with nondiabetic hemodialysis patients. Am J Kidney Dis 2000;35:282-92. |
|54.||Alain GB, Sharon S, Frederick LB. Diabetes and risk of infection-related mortality in the US. Diabetes Care 2001;24:1044-9. |
Anil K Saxena
Division of Nephrology, Department of Medicine, Al-Rahba Hospital - Johns Hopkins Medicine International, P.O. Box 34555, Abu Dhabi
United Arab Emirates
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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