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Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection
Journal of Infection (2014) xx, 1e5
www.elsevierhealth.com/journals/jinf
Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection ´ Luis Del Pozo b, Yolanda Meije a,e, Benito Almirante a,e, Jose ndez-Hidalgo a, Marı´a Teresa Martı´n c, Nuria Ferna a,* Adriana Shan d, Jana Basas a, Albert Pahissa a, Joan Gavalda a
Infectious Diseases Research Laboratory, Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain b Infectious Disease Division, Internal Medicine Department, Clı´nica Universitaria de Navarra, Navarra, Spain c Microbiology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain d Microbiology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain Accepted 1 January 2014 Available online - - -
KEYWORDS Antibiotic-lock therapy; Catheter-related infection; Catheter related bloodstream infection; Daptomycin; Staphylococcus aureus; S. aureus biofilm; Vancomycin
Summary Background: The effectiveness of daptomycin versus vancomycin for treating experimental methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) catheter-related infection by antibiotic-lock technique was assessed. Methods: One MSSA strain and one clinical MRSA isolate were used. A preliminary in vitro study determined the minimum biofilm eradication concentration (MBEC) of vancomycin and daptomycin. An intravenous catheter was implanted in New Zealand white rabbits. Infection was induced by 24 h locking the catheter with 0.3 mL of broth culture containing MSSA or MRSA. The 24 h of antibiotic-lock treatment groups were: control, vancomycin 10 mg/mL, daptomycin 5 mg/mL and daptomycin 50 mg/mL. Results: Daptomycin showed greater in vitro activity than vancomycin against biofilm bacteria (MBECs of vancomycin and daptomycin for MSSA, >2000 mg/L and 7 mg/L; MRSA, >2000 mg/L and 15 mg/L). Daptomycin 5 mg/mL achieved significant reductions relative to vancomycin 10 mg/mL in log10 cfu recovered from catheter tips for both strains (P < 0.05). Only daptomycin 50 mg/mL achieved negative catheter tip cultures (up to 75% in MSSA and 85% in MRSA,
* Corresponding author. Infectious Diseases Department, Hospital Universitari Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel.: þ34 932746090; fax: þ34 934894091. ). E-mail address: [email protected] (J. Gavalda e These authors contributed equally to this work. 0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.01.001 Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
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Y. Meije et al. P < 0.05), showing the greatest median log10 cfu reduction compared to controls (6.07 in MSSA and 6.59 in MRSA, P < 0.05). Conclusions: Daptomycin 50 mg/mL showed the highest activity against both strains biofilms. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Most of catheter-related bloodstream infection (CRBSI) are caused by Staphylococcus epidermidis or Staphylococcus aureus.1 Antibiotic-lock therapy (ALT) combined with a conventional systemic antibiotic is effective treatment for long-term CRBSI, particularly for episodes caused by gram-negative bacilli and coagulase-negative staphylococci.1e3 The antibiotic-lock technique involves instilling a high concentration of antibiotic into the catheter lumen, and allowing it to remain for a period of time.4 However, application of this conservative treatment in S. aureus infections has been questioned. There is substantial evidence that catheter removal is the safest option in this subgroup of cases, since previous studies have shown failure rates of 45%e59% with antibiotic lock.1,5,6 Hence, it is generally accepted that a conservative approach to S. aureus CRBSI with ALT and systemic treatment should be avoided. Nevertheless, ALT has been considered a viable option in selected, hemodynamically stable patients with no other vascular access, and under very close followup.4,7,8 There are no clinical trials investigating treatment of S. aureus CRBSI with the antibiotic-lock technique, and few experimental studies have compared different antimicrobials for conservative management of S. aureus catheterrelated infection (CRI).9,10 In the small number of clinical cases of long-term S. aureus CRBSI described in the literature, vancomycin is the antimicrobial treatment most commonly used.1,5,6 Daptomycin, a lipopeptide with potent, rapid in vitro and in vivo bactericidal activities against methicillinsusceptible (MSSA) and methicillin-resistant S. aureus (MRSA),12 including biofilm-producing strains,13 has been shown to rapidly penetrate staphylococcal biofilms.14 Moreover, daptomycin has a bactericidal activity against the bacterial stationary phase, which is likely to be beneficial in treating biofilms.15 Daptomycin has also demonstrated a faster bactericidal activity than vancomycin.15 Since, features such as host blood flow, serum proteins and other components of the immune system are not accurately reflected in the in vitro models, the present studies describe the development of an in vivo S. aureus model of venous catheter-associated biofilm. The aim of this study was to compare the activity of vancomycin and daptomycin for the treatment of experimental MSSA and MRSA catheter-related infection using the ALT.
Material and methods In vitro studies One MSSA strain (ATCC 6538P) and one clinical MRSA isolate (MRSA 16) were studied. The minimal inhibitory
concentration (MIC) and minimal bactericidal concentration (MBC) of vancomycin and daptomycin for the strains studied were determined with the microdilution technique, following CLSI recommendations for the MIC study.16 The minimum biofilm eradication concentration (MBEC) was defined as the minimum concentration of antimicrobial required to reduce biofilm cell numbers (initial inoculum size) by 99.9%. Biofilm growth was performed as follows: A bead adherence assay was set up in 96-well polystyrene plates with bacterial suspensions (100 mL) between 5 105 and 1 106 CFU/mL. Beads colonized with the bacterial biofilm were placed in serial two-fold dilutions of vancomycin (2000e0.24 mg/L) or daptomycin (2000e0.24 mg/L). Plates were incubated in humidified conditions at 37 C for 24 h. Following incubation, the medium was gently aspirated from each well and replaced three times with sterile 4 C PBS (Merck KGaA, Darmstadt, Germany). Beads were then placed in a solution (1000 mL) containing Mueller-Hinton broth (Becton Dickinson and Company, Sparks, USA). The number of bacteria that adhered to and formed a biofilm on the beads after antimicrobial exposure was determined by vigorously vortexing the beads for 1 min, followed by sonication in an ultrasound bath (40 KHz, 320 mW/cm2) for 5 min. The liquid was serially diluted and bacterial count was determined by the viable count method. All experiments were performed in triplicate.
Animals New Zealand white rabbits weighing 2.0e2.2 kg were used for the in vivo experiments. Upon 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).
Animal model Animals were anesthetized 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 silicone 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 tunneled and brought to the interscapular region. The external portion of the catheter was connected to a removable hub (Vygon 1298.20, Laboratories Pharmaceutiques Vygon, Ecoulen,
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
Daptomycin ALT in S. aureus catheter-related infection France) attached to a disposable port (Sendal TP Inter Minisend, UK) and fixed to the skin. After placement, catheters were inoculated by instillation of 0.3 mL of S. aureus suspension containing 1 108 cfu/mL of either MSSA or MRSA. The strain was subcultured in trypticase soy agar (TSA) for 24 h. Colonies isolated from the subculture were suspended in trypticase 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.
Treatment groups and estimation of therapeutic efficacy The inoculum was locked in the lumen of the catheter for 24 h. Just before starting antibiotic-lock therapy, the inoculum was carefully withdrawn by aspiration. The disposable port and hub were replaced by new devices. Animals were then randomized into the following groups: controls receiving sterile saline, animals receiving 10 mg/ mL of vancomycin (Normon Laboratory S.A., Tres Cantos, Spain), and animals receiving either 5 mg/mL or 50 mg/mL of daptomycin (Novartis Europharm Limited, Horsham, West Sussex, United Kingdom). Daptomycin was dissolved in lactated Ringer’s solution (54 mg/mL calcium [Ca2þ])17 and vancomycin in sterile saline. The concentration of the antibiotic used was the highest possible due to the maximum concentration of the commercial drug vial, 50 mg/mL of daptomycin and 10 mg/mL of vancomycin. Higher concentrations of vancomycin cannot be used due to the precipitation of the drug.18 A second minor concentration that had been previously used in the clinical setting, for Staphylococcus other than S. aureus, was also administered for daptomycin.19 The catheter system was filled with 0.33 mL of antimicrobial solution or sterile saline, as appropriate. All locks were supplemented with 100 IU of sodium heparin/mL. After 24 h of treatment, animals were euthanized by intravenous injection of sodium pentothal, and catheters were removed for microbiological evaluation. The distal 4 cm of the catheter was cut for quantitative culture. The lumen of the catheter segment was gently flushed twice with 2 mL of sterile saline to assure antibiotic removal and the segment was then bisected lengthwise, submerged in 4 mL of sterile saline, and sonicated at 50 Hz for 10 min. The sonication products were washed twice by centrifugation and the pellet was serially diluted, plated, and incubated for colony-forming unit counting onto 5% sheep blood Columbia agar plates for 48 h at 37 C at room atmosphere. After incubation, 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 in each treatment arm was compared using Fisher’s exact test, and the log10 cfu recovered from the catheter tips was compared using the ManneWhitney test. P values <0.05 were considered statistically significant.
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Results In vitro results showed that both strains were susceptible to vancomycin (MSSA, 0.5 mg/mL; MRSA, 1 mg/L) and daptomycin (MSSA, 0.5 mg/L; MRSA, 0.5 mg/L). MBC results were as follows: vancomycin (MSSA, 0.5 mg/L; MRSA, 1 mg/L) and daptomycin (MSSA, 0.5 mg/L; MRSA, 0.5 mg/ L) (Table 1). Vancomycin and daptomycin MBECs for MSSA biofilms were >2000 mg/L and 7 mg/L, respectively. Vancomycin and daptomycin MBECs for MRSA biofilms were >2000 mg/L and 15 mg/L, respectively. Our in vitro studies indicated that vancomycin exerted a limited effect on MSSA and MRSA biofilms. Daptomycin demonstrated better activity against biofilm bacteria than did vancomycin. Results obtained from catheter tip cultures are shown in Table 2. As compared to the controls, daptomycin 50 mg/ mL achieved a significant reduction of more than 6 log10 cfu recovered from the catheter tips in MSSA (6.07 P 0.001) and MRSA (6.59 P 0.001) at 24 h. Colony counts were significantly lower in animals treated with daptomycin 50 mg/mL lock therapy than those with vancomycin lock (MSSA and MRSA; both, P 0.001). Furthermore, daptomycin 50 mg/mL lock achieved much lower counts than daptomycin 5 mg/mL for MSSA (P < 0.05) and MRSA (P < 0.001). Of note, daptomycin 50 mg/mL was the only antibiotic achieving a significant percentage of negative catheter cultures in both strains after 24 h of antibiotic lock: 75% in MSSA (controls 0%; daptomycin 5 mg/mL 28%; vancomycin 10 mg/mL 8%; P < 0.05) and 85% in MRSA (controls 0%; daptomycin 5 mg/mL 0%; vancomycin 10 mg/mL 0%; P < 0.001).
Discussion This study assessed the effectiveness of high doses of daptomycin versus low doses of daptomycin or vancomycin for the treatment of experimental S. aureus CRI using ALT. Focusing on MSSA, although daptomycin 5 mg/mL was more effective than vancomycin at reducing MSSA strain colony counts from catheters, high-dose daptomycin at 50 mg/ mL ALT achieved the highest activity against MSSA, reaching negative catheter tip culture in the majority of cases. With regard to MRSA, daptomycin at 5 mg/mL achieved statistically better results than vancomycin 10 mg/mL, but daptomycin at 50 mg/mL again provided the best outcomes, with the highest rates of negative catheter tip cultures. The concentration of the antibiotic used was the highest possible due to the maximum concentration of the commercial drug vial, higher concentrations of vancomycin cannot be used due to the precipitation of the drug.18 Therefore, daptomycin at 50 mg/mL was the antibiotic and dose showing the greatest activity and highest percentage of negative cultures against both MSSA and MRSA strains at 24 of ALT in the CRI model used. Rapid clearance of the pathogen in an infected central venous catheter would likely be important clinically, especially in the case of S. aureus, if the catheter could be kept in place. This effect was obtained with 50 mg/mL daptomycin lock therapy for 24 h in our model. The results of our
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
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Y. Meije et al. Table 1
Susceptibility of the two strains to vancomycin and daptomycin.
Strain
Vancomycin
Daptomycin
MIC
MBC
MBEC
MIC
MBC
MBEC
MSSA ATCC 6538P
0.5 mg/L
0.5 mg/L
>2000 mg/L
0.5 mg/L
0.5 mg/L
7 mg/L
MRSA 16 C
1 mg/L
1 mg/L
>2000 mg/L
0.5 mg/L
0.5 mg/L
15 mg/L
MBC, minimal bactericidal concentration; MBEC, minimum biofilm eradication concentration; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
Table 2
Results of treatment for Staphylococcus aureus experimental catheter-related infection.
Treatment
Control Daptomycin 50 Daptomycin 5 Vancomycin 10
S. aureus MSSA ATCC 6538P
S. aureus MRSA 16
Negative cultures/ total (%)
log10 total cfu median (IQR)
Negative cultures/ total (%)
log10 total cfu median (IQR)
0/12 9/12 3/11 1/12
6.07 0 1.27 3.61
0/14 (0) 11/13 (85)a 0/8 (0) 0/13 (0)
6.59 0 3.36 4.80
(0) (75)a (28) (8)
(5.55e6.73) (0e0.58)a (0.07e2.18)b (2.56e4.43)c
(6.19e7.40) (0e0)a (2.66e4.83)b (3.82e5.90)
cfu, colony-forming units; daptomycin 50, daptomycin 50 mg/mL; daptomycin 5, daptomycin 5 mg/mL; IQR, interquartile range; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; vancomycin 10, vancomycin 10 mg/ mL. a P < 0.05 vs control, daptomycin 5 mg/mL and vancomycin 10 mg/mL. b P < 0.05 vs control and vancomycin 10 mg/mL. c P < 0.05 vs control.
experiments are in concordance with those of Van Praagh et al.17 in a rat model, although there are some dissimilarities in the experimental variables. In the study by these authors, combined daptomycin ALT and systemic dosing resulted in clearance of MSSA infection after two daily ALT treatments (30 min with daptomycin at 5 mg/mL). The weak activity of vancomycin seen in our experiments was in keeping with the findings of Giacometti et al.11 in an S. aureus experimental model, in which one week of vancomycin ALT did not achieve negative catheter tip cultures. Daptomycin and vancomycin have also been investigated using in vitro biofilm models. Our study showed that planktonic MIC and MBC were not feasible measures of the antimicrobial activity in biofilm, as has been reported previously.20 The drug concentrations required to eradicate bacteria in the biofilm were much higher than the values obtained in planktonic cultures. MBEC results showed the need for higher vancomycin concentrations than the ALT doses, which was not the case for daptomycin. Daptomycin ALT has been shown to act faster and more effectively than vancomycin or other antibiotics against MSSA and MRSA biofilm-forming strains,21e25 whereas vancomycin ALT has failed to eradicate biofilm-embedded S. aureus isolates.10,22,23 These findings suggest that daptomycin rapidly penetrates the biofilm layer, as has been reported by Stewart et al.14 In contrast, the weak activity of vancomycin may be partially due to a reduced penetration rate in S. aureus biofilm.26 This could be the result of a reaction with components of the biofilm matrix, hindering penetration. S. aureus and S. epidermidis slime has been found to remarkably decrease the activity of the glycopeptides, vancomycin and teicoplanin.27 To date, this effect has not been evaluated for daptomycin.
There is little published experience on conservative management of S. aureus CRBSI in humans.1,5,6 Most studies exclude these cases because of high reported failure rates (up to 59%).1,5,6 Although it is well recognized that the safest option for these patients is to remove the catheter, this measure is not always possible (no alternative venous access, significant bleeding diathesis, or quality of life issues taking priority over the need for reinsertion of a new catheter at another site).7 Even in pediatrics, where it is sometimes very difficult to establish a central line, some authorities have recommended trying in situ treatment for 72 h when the patient shows no clinical deterioration.8 Del Pozo et al.19 reported successful outcomes with the use of daptomycin at 5 mg/mL. However, this dose did not suffice to achieve negative catheter cultures at 24 h in our model of S. aureus CRBSI. We consider 24 h of treatment the turning point to clinically maintain long-term outcomes and avoid possible complications of infection, and in the present study, daptomycin ALT at 50 mg/mL was needed to achieve a higher percentage of negative tip catheter cultures at that time point. In the literature, vancomycin is the most widely used antimicrobial for treating long-term S. aureus CRBSI by ALT.7,8 Based on our results and the previous evidence of vancomycin’s weak activity for this purpose, daptomycin may prove to be a useful alternative, providing a fast decrease in biofilm-embedded S. aureus and achieving negative catheter tip cultures in 24 h for the majority of episodes.
Acknowledgments This study was supported by Ministerio de Economı´a y Competitividad, Instituto de Salud Carlos III e co-financed
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
Daptomycin ALT in S. aureus catheter-related infection
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by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015) and Novartis Farmace ´utica ~a. We are grateful to Celine Cavallo for English lanEspan guage support.
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1. Fernandez-Hidalgo N, Almirante B, Calleja R, Ruiz I, Planes AM, Rodriguez D, et al. Antibiotic-lock therapy for long-term intravascular catheter-related bacteraemia: results of an open, non-comparative study. J Antimicrob Chemother 2006;57: 1172e80. 2. Funalleras G, Fernandez-Hidalgo N, Borrego A, Almirante B, Planes AM, Rodriguez D, et al. Effectiveness of antibioticlock therapy for long-term catheter-related bacteremia due to Gram-negative bacilli: a prospective observational study. Clin Infect Dis 2011;53:e129e32. 3. Rijnders BJ, Van Wijngaerden E, Vandecasteele SJ, Stas M, Peetermans WE. Treatment of long-term intravascular catheter-related bacteraemia with antibiotic lock: randomized, placebo-controlled trial. J Antimicrob Chemother 2005; 55:90e4. 4. Carratala J. The antibiotic-lock technique for therapy of ’highly needed’ infected catheters. Clin Microbiol Infect 2002;8: 282e9. 5. Fortun J, Grill F, Martin-Davila P, Blazquez J, Tato M, SanchezCorral J, et al. Treatment of long-term intravascular catheterrelated bacteraemia with antibiotic-lock therapy. J Antimicrob Chemother 2006;58:816e21. 6. Maya ID, Carlton D, Estrada E, Allon M. Treatment of dialysis catheter-related Staphylococcus aureus bacteremia with an antibiotic lock: a quality improvement report. Am J Kidney Dis 2007;50:289e95. 7. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1e45. 8. Simon A, Bode U, Beutel K. Diagnosis and treatment of catheter-related infections in paediatric oncology: an update. Clin Microbiol Infect 2006;12:606e20. 9. Capdevila JA, Gavalda J, Fortea J, Lopez P, Martin MT, Gomis X, 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;7:206e12. 10. Fernandez-Hidalgo N, Gavalda J, Almirante B, Martin MT, Onrubia PL, Gomis X, et al. Evaluation of linezolid, vancomycin, gentamicin and ciprofloxacin in a rabbit model of antibiotic-lock technique for Staphylococcus aureus catheterrelated infection. J Antimicrob Chemother 2010;65:525e30. 11. Giacometti A, Cirioni O, Ghiselli R, Orlando F, Mocchegiani F, Silvestri C, et al. Comparative efficacies of quinupristindalfopristin, linezolid, vancomycin, and ciprofloxacin in treatment, using the antibiotic-lock technique, of experimental catheter-related infection due to Staphylococcus aureus. Antimicrob Agents Chemother 2005;49:4042e5. 12. Sader HS, Farrell DJ, Jones RN. Antimicrobial activity of daptomycin tested against gram-positive strains collected in
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European hospitals: results from 7 years of resistance surveillance (2003e2009). J Chemother 2011;23:200e6. Smith K, Perez A, Ramage G, Gemmell CG, Lang S. Comparison of biofilm-associated cell survival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to the antibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin. Int J Antimicrob Agents 2009;33:374e8. Stewart PS, Davison WM, Steenbergen JN. Daptomycin rapidly penetrates a Staphylococcus epidermidis biofilm. Antimicrob Agents Chemother 2009;53:3505e7. Mascio CT, Alder JD, Silverman JA. Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrob Agents Chemother 2007;51: 4255e60. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard M7eA7. Wayne, PA, USA: CLSI; 2006. Van Praagh AD, Li T, Zhang S, Arya A, Chen L, Zhang XX, et al. Daptomycin antibiotic lock therapy in a rat model of staphylococcal central venous catheter biofilm infections. Antimicrob Agents Chemother 2011;55:4081e9. Del Pozo JL. Role of antibiotic lock therapy for the treatment of catheter-related bloodstream infections. Int J Artif Organs 2009;32:678e88. Del Pozo JL, Rodil R, Aguinaga A, Yuste JR, Bustos C, Montero A, et al. Daptomycin lock therapy for grampositive long-term catheter-related bloodstream infections. Int J Clin Pract 2012;66:305e8. Parra-Ruiz J, Vidaillac C, Rose WE, Rybak MJ. Activities of highdose daptomycin, vancomycin, and moxifloxacin alone or in combination with clarithromycin or rifampin in a novel in vitro model of Staphylococcus aureus biofilm. Antimicrob Agents Chemother 2010;54:4329e34. Bookstaver PB, Williamson JC, Tucker BK, Raad II, Sherertz RJ. Activity of novel antibiotic lock solutions in a model against isolates of catheter-related bloodstream infections. Ann Pharmacother 2009;43:210e9. LaPlante KL, Mermel LA. In vitro activity of daptomycin and vancomycin lock solutions on staphylococcal biofilms in a central venous catheter model. Nephrol Dial Transplant 2007;22: 2239e46. Raad I, Hanna H, Jiang Y, Dvorak T, Reitzel R, Chaiban G, et al. Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm. Antimicrob Agents Chemother 2007;51:1656e60. Rose WE, Poppens PT. Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus. J Antimicrob Chemother 2009;63:485e8. Roveta S, Marchese A, Schito GC. Activity of daptomycin on biofilms produced on a plastic support by Staphylococcus spp. Int J Antimicrob Agents 2008;31:321e8. Singh R, Ray P, Das A, Sharma M. Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Antimicrob Chemother 2010;65:1955e8. Mathur T, Singhal S, Khan S, Upadhyay D, Fatma T, Rattan A. Adverse effect of staphylococci slime on in vitro activity of glycopeptides. Jpn J Infect Dis 2005;58:353e7.
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
www.elsevierhealth.com/journals/jinf
Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection ´ Luis Del Pozo b, Yolanda Meije a,e, Benito Almirante a,e, Jose ndez-Hidalgo a, Marı´a Teresa Martı´n c, Nuria Ferna a,* Adriana Shan d, Jana Basas a, Albert Pahissa a, Joan Gavalda a
Infectious Diseases Research Laboratory, Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain b Infectious Disease Division, Internal Medicine Department, Clı´nica Universitaria de Navarra, Navarra, Spain c Microbiology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain d Microbiology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain Accepted 1 January 2014 Available online - - -
KEYWORDS Antibiotic-lock therapy; Catheter-related infection; Catheter related bloodstream infection; Daptomycin; Staphylococcus aureus; S. aureus biofilm; Vancomycin
Summary Background: The effectiveness of daptomycin versus vancomycin for treating experimental methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) catheter-related infection by antibiotic-lock technique was assessed. Methods: One MSSA strain and one clinical MRSA isolate were used. A preliminary in vitro study determined the minimum biofilm eradication concentration (MBEC) of vancomycin and daptomycin. An intravenous catheter was implanted in New Zealand white rabbits. Infection was induced by 24 h locking the catheter with 0.3 mL of broth culture containing MSSA or MRSA. The 24 h of antibiotic-lock treatment groups were: control, vancomycin 10 mg/mL, daptomycin 5 mg/mL and daptomycin 50 mg/mL. Results: Daptomycin showed greater in vitro activity than vancomycin against biofilm bacteria (MBECs of vancomycin and daptomycin for MSSA, >2000 mg/L and 7 mg/L; MRSA, >2000 mg/L and 15 mg/L). Daptomycin 5 mg/mL achieved significant reductions relative to vancomycin 10 mg/mL in log10 cfu recovered from catheter tips for both strains (P < 0.05). Only daptomycin 50 mg/mL achieved negative catheter tip cultures (up to 75% in MSSA and 85% in MRSA,
* Corresponding author. Infectious Diseases Department, Hospital Universitari Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel.: þ34 932746090; fax: þ34 934894091. ). E-mail address: [email protected] (J. Gavalda e These authors contributed equally to this work. 0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.01.001 Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
2
Y. Meije et al. P < 0.05), showing the greatest median log10 cfu reduction compared to controls (6.07 in MSSA and 6.59 in MRSA, P < 0.05). Conclusions: Daptomycin 50 mg/mL showed the highest activity against both strains biofilms. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Most of catheter-related bloodstream infection (CRBSI) are caused by Staphylococcus epidermidis or Staphylococcus aureus.1 Antibiotic-lock therapy (ALT) combined with a conventional systemic antibiotic is effective treatment for long-term CRBSI, particularly for episodes caused by gram-negative bacilli and coagulase-negative staphylococci.1e3 The antibiotic-lock technique involves instilling a high concentration of antibiotic into the catheter lumen, and allowing it to remain for a period of time.4 However, application of this conservative treatment in S. aureus infections has been questioned. There is substantial evidence that catheter removal is the safest option in this subgroup of cases, since previous studies have shown failure rates of 45%e59% with antibiotic lock.1,5,6 Hence, it is generally accepted that a conservative approach to S. aureus CRBSI with ALT and systemic treatment should be avoided. Nevertheless, ALT has been considered a viable option in selected, hemodynamically stable patients with no other vascular access, and under very close followup.4,7,8 There are no clinical trials investigating treatment of S. aureus CRBSI with the antibiotic-lock technique, and few experimental studies have compared different antimicrobials for conservative management of S. aureus catheterrelated infection (CRI).9,10 In the small number of clinical cases of long-term S. aureus CRBSI described in the literature, vancomycin is the antimicrobial treatment most commonly used.1,5,6 Daptomycin, a lipopeptide with potent, rapid in vitro and in vivo bactericidal activities against methicillinsusceptible (MSSA) and methicillin-resistant S. aureus (MRSA),12 including biofilm-producing strains,13 has been shown to rapidly penetrate staphylococcal biofilms.14 Moreover, daptomycin has a bactericidal activity against the bacterial stationary phase, which is likely to be beneficial in treating biofilms.15 Daptomycin has also demonstrated a faster bactericidal activity than vancomycin.15 Since, features such as host blood flow, serum proteins and other components of the immune system are not accurately reflected in the in vitro models, the present studies describe the development of an in vivo S. aureus model of venous catheter-associated biofilm. The aim of this study was to compare the activity of vancomycin and daptomycin for the treatment of experimental MSSA and MRSA catheter-related infection using the ALT.
Material and methods In vitro studies One MSSA strain (ATCC 6538P) and one clinical MRSA isolate (MRSA 16) were studied. The minimal inhibitory
concentration (MIC) and minimal bactericidal concentration (MBC) of vancomycin and daptomycin for the strains studied were determined with the microdilution technique, following CLSI recommendations for the MIC study.16 The minimum biofilm eradication concentration (MBEC) was defined as the minimum concentration of antimicrobial required to reduce biofilm cell numbers (initial inoculum size) by 99.9%. Biofilm growth was performed as follows: A bead adherence assay was set up in 96-well polystyrene plates with bacterial suspensions (100 mL) between 5 105 and 1 106 CFU/mL. Beads colonized with the bacterial biofilm were placed in serial two-fold dilutions of vancomycin (2000e0.24 mg/L) or daptomycin (2000e0.24 mg/L). Plates were incubated in humidified conditions at 37 C for 24 h. Following incubation, the medium was gently aspirated from each well and replaced three times with sterile 4 C PBS (Merck KGaA, Darmstadt, Germany). Beads were then placed in a solution (1000 mL) containing Mueller-Hinton broth (Becton Dickinson and Company, Sparks, USA). The number of bacteria that adhered to and formed a biofilm on the beads after antimicrobial exposure was determined by vigorously vortexing the beads for 1 min, followed by sonication in an ultrasound bath (40 KHz, 320 mW/cm2) for 5 min. The liquid was serially diluted and bacterial count was determined by the viable count method. All experiments were performed in triplicate.
Animals New Zealand white rabbits weighing 2.0e2.2 kg were used for the in vivo experiments. Upon 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).
Animal model Animals were anesthetized 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 silicone 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 tunneled and brought to the interscapular region. The external portion of the catheter was connected to a removable hub (Vygon 1298.20, Laboratories Pharmaceutiques Vygon, Ecoulen,
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
Daptomycin ALT in S. aureus catheter-related infection France) attached to a disposable port (Sendal TP Inter Minisend, UK) and fixed to the skin. After placement, catheters were inoculated by instillation of 0.3 mL of S. aureus suspension containing 1 108 cfu/mL of either MSSA or MRSA. The strain was subcultured in trypticase soy agar (TSA) for 24 h. Colonies isolated from the subculture were suspended in trypticase 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.
Treatment groups and estimation of therapeutic efficacy The inoculum was locked in the lumen of the catheter for 24 h. Just before starting antibiotic-lock therapy, the inoculum was carefully withdrawn by aspiration. The disposable port and hub were replaced by new devices. Animals were then randomized into the following groups: controls receiving sterile saline, animals receiving 10 mg/ mL of vancomycin (Normon Laboratory S.A., Tres Cantos, Spain), and animals receiving either 5 mg/mL or 50 mg/mL of daptomycin (Novartis Europharm Limited, Horsham, West Sussex, United Kingdom). Daptomycin was dissolved in lactated Ringer’s solution (54 mg/mL calcium [Ca2þ])17 and vancomycin in sterile saline. The concentration of the antibiotic used was the highest possible due to the maximum concentration of the commercial drug vial, 50 mg/mL of daptomycin and 10 mg/mL of vancomycin. Higher concentrations of vancomycin cannot be used due to the precipitation of the drug.18 A second minor concentration that had been previously used in the clinical setting, for Staphylococcus other than S. aureus, was also administered for daptomycin.19 The catheter system was filled with 0.33 mL of antimicrobial solution or sterile saline, as appropriate. All locks were supplemented with 100 IU of sodium heparin/mL. After 24 h of treatment, animals were euthanized by intravenous injection of sodium pentothal, and catheters were removed for microbiological evaluation. The distal 4 cm of the catheter was cut for quantitative culture. The lumen of the catheter segment was gently flushed twice with 2 mL of sterile saline to assure antibiotic removal and the segment was then bisected lengthwise, submerged in 4 mL of sterile saline, and sonicated at 50 Hz for 10 min. The sonication products were washed twice by centrifugation and the pellet was serially diluted, plated, and incubated for colony-forming unit counting onto 5% sheep blood Columbia agar plates for 48 h at 37 C at room atmosphere. After incubation, 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 in each treatment arm was compared using Fisher’s exact test, and the log10 cfu recovered from the catheter tips was compared using the ManneWhitney test. P values <0.05 were considered statistically significant.
3
Results In vitro results showed that both strains were susceptible to vancomycin (MSSA, 0.5 mg/mL; MRSA, 1 mg/L) and daptomycin (MSSA, 0.5 mg/L; MRSA, 0.5 mg/L). MBC results were as follows: vancomycin (MSSA, 0.5 mg/L; MRSA, 1 mg/L) and daptomycin (MSSA, 0.5 mg/L; MRSA, 0.5 mg/ L) (Table 1). Vancomycin and daptomycin MBECs for MSSA biofilms were >2000 mg/L and 7 mg/L, respectively. Vancomycin and daptomycin MBECs for MRSA biofilms were >2000 mg/L and 15 mg/L, respectively. Our in vitro studies indicated that vancomycin exerted a limited effect on MSSA and MRSA biofilms. Daptomycin demonstrated better activity against biofilm bacteria than did vancomycin. Results obtained from catheter tip cultures are shown in Table 2. As compared to the controls, daptomycin 50 mg/ mL achieved a significant reduction of more than 6 log10 cfu recovered from the catheter tips in MSSA (6.07 P 0.001) and MRSA (6.59 P 0.001) at 24 h. Colony counts were significantly lower in animals treated with daptomycin 50 mg/mL lock therapy than those with vancomycin lock (MSSA and MRSA; both, P 0.001). Furthermore, daptomycin 50 mg/mL lock achieved much lower counts than daptomycin 5 mg/mL for MSSA (P < 0.05) and MRSA (P < 0.001). Of note, daptomycin 50 mg/mL was the only antibiotic achieving a significant percentage of negative catheter cultures in both strains after 24 h of antibiotic lock: 75% in MSSA (controls 0%; daptomycin 5 mg/mL 28%; vancomycin 10 mg/mL 8%; P < 0.05) and 85% in MRSA (controls 0%; daptomycin 5 mg/mL 0%; vancomycin 10 mg/mL 0%; P < 0.001).
Discussion This study assessed the effectiveness of high doses of daptomycin versus low doses of daptomycin or vancomycin for the treatment of experimental S. aureus CRI using ALT. Focusing on MSSA, although daptomycin 5 mg/mL was more effective than vancomycin at reducing MSSA strain colony counts from catheters, high-dose daptomycin at 50 mg/ mL ALT achieved the highest activity against MSSA, reaching negative catheter tip culture in the majority of cases. With regard to MRSA, daptomycin at 5 mg/mL achieved statistically better results than vancomycin 10 mg/mL, but daptomycin at 50 mg/mL again provided the best outcomes, with the highest rates of negative catheter tip cultures. The concentration of the antibiotic used was the highest possible due to the maximum concentration of the commercial drug vial, higher concentrations of vancomycin cannot be used due to the precipitation of the drug.18 Therefore, daptomycin at 50 mg/mL was the antibiotic and dose showing the greatest activity and highest percentage of negative cultures against both MSSA and MRSA strains at 24 of ALT in the CRI model used. Rapid clearance of the pathogen in an infected central venous catheter would likely be important clinically, especially in the case of S. aureus, if the catheter could be kept in place. This effect was obtained with 50 mg/mL daptomycin lock therapy for 24 h in our model. The results of our
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
4
Y. Meije et al. Table 1
Susceptibility of the two strains to vancomycin and daptomycin.
Strain
Vancomycin
Daptomycin
MIC
MBC
MBEC
MIC
MBC
MBEC
MSSA ATCC 6538P
0.5 mg/L
0.5 mg/L
>2000 mg/L
0.5 mg/L
0.5 mg/L
7 mg/L
MRSA 16 C
1 mg/L
1 mg/L
>2000 mg/L
0.5 mg/L
0.5 mg/L
15 mg/L
MBC, minimal bactericidal concentration; MBEC, minimum biofilm eradication concentration; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
Table 2
Results of treatment for Staphylococcus aureus experimental catheter-related infection.
Treatment
Control Daptomycin 50 Daptomycin 5 Vancomycin 10
S. aureus MSSA ATCC 6538P
S. aureus MRSA 16
Negative cultures/ total (%)
log10 total cfu median (IQR)
Negative cultures/ total (%)
log10 total cfu median (IQR)
0/12 9/12 3/11 1/12
6.07 0 1.27 3.61
0/14 (0) 11/13 (85)a 0/8 (0) 0/13 (0)
6.59 0 3.36 4.80
(0) (75)a (28) (8)
(5.55e6.73) (0e0.58)a (0.07e2.18)b (2.56e4.43)c
(6.19e7.40) (0e0)a (2.66e4.83)b (3.82e5.90)
cfu, colony-forming units; daptomycin 50, daptomycin 50 mg/mL; daptomycin 5, daptomycin 5 mg/mL; IQR, interquartile range; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; vancomycin 10, vancomycin 10 mg/ mL. a P < 0.05 vs control, daptomycin 5 mg/mL and vancomycin 10 mg/mL. b P < 0.05 vs control and vancomycin 10 mg/mL. c P < 0.05 vs control.
experiments are in concordance with those of Van Praagh et al.17 in a rat model, although there are some dissimilarities in the experimental variables. In the study by these authors, combined daptomycin ALT and systemic dosing resulted in clearance of MSSA infection after two daily ALT treatments (30 min with daptomycin at 5 mg/mL). The weak activity of vancomycin seen in our experiments was in keeping with the findings of Giacometti et al.11 in an S. aureus experimental model, in which one week of vancomycin ALT did not achieve negative catheter tip cultures. Daptomycin and vancomycin have also been investigated using in vitro biofilm models. Our study showed that planktonic MIC and MBC were not feasible measures of the antimicrobial activity in biofilm, as has been reported previously.20 The drug concentrations required to eradicate bacteria in the biofilm were much higher than the values obtained in planktonic cultures. MBEC results showed the need for higher vancomycin concentrations than the ALT doses, which was not the case for daptomycin. Daptomycin ALT has been shown to act faster and more effectively than vancomycin or other antibiotics against MSSA and MRSA biofilm-forming strains,21e25 whereas vancomycin ALT has failed to eradicate biofilm-embedded S. aureus isolates.10,22,23 These findings suggest that daptomycin rapidly penetrates the biofilm layer, as has been reported by Stewart et al.14 In contrast, the weak activity of vancomycin may be partially due to a reduced penetration rate in S. aureus biofilm.26 This could be the result of a reaction with components of the biofilm matrix, hindering penetration. S. aureus and S. epidermidis slime has been found to remarkably decrease the activity of the glycopeptides, vancomycin and teicoplanin.27 To date, this effect has not been evaluated for daptomycin.
There is little published experience on conservative management of S. aureus CRBSI in humans.1,5,6 Most studies exclude these cases because of high reported failure rates (up to 59%).1,5,6 Although it is well recognized that the safest option for these patients is to remove the catheter, this measure is not always possible (no alternative venous access, significant bleeding diathesis, or quality of life issues taking priority over the need for reinsertion of a new catheter at another site).7 Even in pediatrics, where it is sometimes very difficult to establish a central line, some authorities have recommended trying in situ treatment for 72 h when the patient shows no clinical deterioration.8 Del Pozo et al.19 reported successful outcomes with the use of daptomycin at 5 mg/mL. However, this dose did not suffice to achieve negative catheter cultures at 24 h in our model of S. aureus CRBSI. We consider 24 h of treatment the turning point to clinically maintain long-term outcomes and avoid possible complications of infection, and in the present study, daptomycin ALT at 50 mg/mL was needed to achieve a higher percentage of negative tip catheter cultures at that time point. In the literature, vancomycin is the most widely used antimicrobial for treating long-term S. aureus CRBSI by ALT.7,8 Based on our results and the previous evidence of vancomycin’s weak activity for this purpose, daptomycin may prove to be a useful alternative, providing a fast decrease in biofilm-embedded S. aureus and achieving negative catheter tip cultures in 24 h for the majority of episodes.
Acknowledgments This study was supported by Ministerio de Economı´a y Competitividad, Instituto de Salud Carlos III e co-financed
Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001
Daptomycin ALT in S. aureus catheter-related infection
5
by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015) and Novartis Farmace ´utica ~a. We are grateful to Celine Cavallo for English lanEspan guage support.
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Please cite this article in press as: Meije Y, et al., Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.01.001