AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sherertz, R. J.
Right arrow Articles by Raad, I. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sherertz, R. J.
Right arrow Articles by Raad, I. I.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2006, p. 1865-1868, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1865-1868.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Comparative In Vitro Efficacies of Various Catheter Lock Solutions

Robert J. Sherertz,1* Michael S. Boger,1 Casey A. Collins,1 Lori Mason,2 and Issam I. Raad3

Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina,1 Department of Infection Control, North Carolina Baptist Hospital, Winston-Salem, North Carolina,2 Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas3

Received 17 January 2006/ Accepted 17 February 2006


   ABSTRACT
Top
 Abstract
Text
 References
 
MEDTA (minocycline-edetate calcium disodium), taurolidine (2%)-polyvinylpyrolidine (5%) (T/PVP), and ethanol as potential catheter lock solutions have a unique mechanism of action, broad-spectrum activity, and anticoagulant properties. Traditional lock solutions minocycline (M), rifampin (R), ciprofloxacin (C), and vancomycin, except pharmacologic concentrations of C and R and of M and R, were less effective than MEDTA and T/PVP.


   TEXT
Top
 Abstract
 Text
References
 
Systemic antibiotics alone eradicate only approximately one-third of catheter-related bloodstream infections (20); catheter replacement, often difficult, is usually required (4, 43). Most long-term catheter infections originate in the lumen, where systemic antibiotics do not reach (39). Killing organisms in biofilm requires antibiotic concentrations that systemic therapy cannot deliver (22, 32). A number of studies illustrate that filling a catheter lumen with high concentrations of antibiotics (lock technique) can eradicate bacteria, improving catheter salvage rates.

Minocycline-edetate calcium disodium (MEDTA) (7, 11, 25, 27, 30), taurolidine-polyvinylpyrolidine (T/PVP) (2, 6, 33, 38, 45), and ethanol (E) (14, 21, 23) are promising lock solutions. We examined the relative efficacies of vancomycin (V), ciprofloxacin (C), minocycline (M), minocycline-rifampin (M/R), ciprofloxacin-rifampin (C/R), vancomycin-rifampin (V/R), E, EDTA, MEDTA, and T/PVP at killing Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans growing in biofilms.

Silicone Hickman catheter segments (1 cm) were incubated overnight at 37°C in tryptic soy broth (two to four replicates per condition) for growth of each organism. Segments were removed, rinsed thrice in phosphate-buffered saline (PBS), and incubated in various lock solutions for 0, 2, 4, or 24 h at 37°C. Segments were removed, washed 10 times in PBS, placed in tryptic soy broth, sonicated for 3 min, vortexed for 10 s, serially diluted, and plated on blood agar. CFU were counted after 24 h of incubation at 37°C and converted to log 10 values. Each experiment was duplicated. Values were averaged, and the means were graphed. Results at 24 h were compared using analysis of variance and Student's t test (Minitab, Penn State University, PA).

The most common causative organisms of vascular catheter infections are S. epidermidis, S. aureus, and yeasts, including C. albicans (18). P. aeruginosa causes severe, often difficult-to-eradicate bloodstream infections. We used the P1 S. aureus strain (13, 39), the slime-producing RP62A S. epidermidis strain (12), and P. aeruginosa and C. albicans catheter-related bloodstream infection isolates. MICs (in micrograms per milliliters) were determined for M, R, C, and V: for S. aureus, MICs were ≤0.5, ≤0.12, ≤0.12, and ≤0.5, respectively; for S. epidermidis, MICs were ≤0.5, ≤0.12, 0.25, and 1.0; for P. aeruginosa, MICs were 4.0, >4.0, ≤0.12, and >16.0; and for C. albicans, MICs were 2.0, >8.0, >2.0, and >16.0. The following lock solutions were investigated: the therapeutic concentration (attainable serum concentration) (31, 40, 46, 48) for M was 2 µg/ml, for R was 5 µg/ml, for C was 2 µg/ml, for V was 20 µg/ml (used individually or as M/R, C/R, and V/R); the pharmacologic concentration for M was 3 mg/ml, for C was 3 mg/ml, for R was 3 mg/ml, and for V was 3 mg/ml (used individually or as M/R, C/R, and V/R); and the pharmacologic concentrations for T/PVP were 2% T and 5% PVP, for MEDTA were 3 mg/ml M and 30 mg/ml EDTA, and for ethyl alcohol were 10%, 20%, 30%, 50%, 70%, and 100% (±30 mg/ml EDTA).

For S. aureus, therapeutic concentrations of antibiotics (±R), except V/R, significantly reduced CFU (log 10) removed by sonication at 24 h versus PBS results (1 to 2 log units [P < 0.05]) (Fig. 1A). With C. albicans, analysis of variance detected no significant differences compared to PBS results (P > 0.05) (Fig. 1B). For S. aureus, at pharmacologic concentrations, M, R, M/R, C/R, MEDTA, or T/PVP (2.8 to 3.5 log units [P < 0.001]) was significantly more effective than V, V/R, or C (0.7 to 1.2 log units) at reducing 24 h CFU versus the PBS control results (Fig. 2A). V antagonized the effect of R at 2, 4, and 24 h (P < 0.05). The combinations M/R, C/R, MEDTA, and T/PVP at pharmacologic concentrations were superior to all therapeutic concentrations against S. aureus (P < 0.05).


Figure 1
View larger version (12K):
[in this window]
[in a new window]
  		FIG. 1. Effects of therapeutic concentrations of antibiotic lock solutions on the growth of S. aureus (A) and C. albicans (B). M, minocycline; C, ciprofloxacin; V, vancomycin; R, rifampin; M + R, minocycline plus rifampin; C + R, ciprofloxacin plus rifampin; V + R, vancomycin plus rifampin.

 

Figure 2
View larger version (15K):
[in this window]
[in a new window]
  		FIG. 2. Effects of pharmacologic concentrations of antibiotic lock solutions on the growth of S. aureus (A), S. epidermidis (B), P. aeruginosa (C), and C. albicans (D). M, minocycline; C, ciprofloxacin; V, vancomycin; R, rifampin; M + R, minocycline plus rifampin; C + R, ciprofloxacin plus rifampin; V + R, vancomycin plus rifampin; T 2%, PVP 5%, 2% taurolidine-5% polyvinylpyrolidine; MEDTA, minocycline-edetate calcium disodium.

 
All agents killed S. epidermidis (2.4 to 3.5 log units [P < 0.001]) (Fig. 2B) and P. aeruginosa (2.1 to 4.7 log units [P = 0.007]) (Fig. 2C) at 24 h. With C. albicans, MEDTA, T/PVP, C, C/R, and M/R showed significant killing at 24 h versus PBS results (2.0 to 2.6 log units [P = 0.003]) (Fig. 2D). With C. albicans, M/R, C/R, and MEDTA demonstrated synergy compared to the results seen with each agent individually (P < 0.001). All ethanol concentrations produced 3.6 to 3.9 log units of killing of S. aureus at 2 and 4 h, superior to all other single and combination lock solutions (data not shown). This effect was maintained for 24 h.

Despite being the most extensively studied antibiotic lock solution (9, 10, 19, 35, 37), vancomycin was the least efficacious agent in our study. It lacks significant activity toward organisms in biofilm (30). One concern with vancomycin lock solutions is the risk of resistant organisms. Since other agents were at least as effective, vancomycin does not appear to be an ideal lock solution.

EDTA has broad-spectrum activity; its complex mechanism of action makes resistance doubtful (7, 34). Minocycline and EDTA are synergistic; no toxicities have been reported. MEDTA, when used in concentrations similar to that used in our study, was undetectable in serum (25). Taurolidine has novel activity, making resistance unlikely (5, 8, 16, 17, 45). It is bactericidal with broad-spectrum activity (38). The only significant adverse reactions reported occurred with high intravenous doses, including dose-related, reversible thrombocytopenia and neutropenia (1). It is unlikely that significant toxicities would occur with taurolidine as a lock solution.

Ethanol has broad-spectrum antimicrobial activity based on denaturization rather than a specific molecular target, making resistance unlikely (36). It may reduce the use of broad-spectrum antibiotics and eradicate organisms otherwise difficult to clear. Ethanol combined with antibiotics in lock solutions could be synergistic. Mild side effects—fatigue, headache, dizziness, nausea, and light-headedness—were noted when ethanol was used as a lock solution (14). Theoretical toxicities (central nervous system depression, arrhythmias, flushing, local venous irritation) are unlikely when ethanol is used as a lock solution (3, 15). Ethanol concentrations as low as 30% were effective in our study, although higher concentrations have been thought necessary to inhibit biofilm growth (41).

Thrombosis is a major reason for catheter loss. Ethanol is effective at restoring catheter patency (23, 24, 28, 44, 47). MEDTA, taurolidine, and ethanol lock solutions appear to have intrinsic anticoagulant activity; they may prevent catheter thrombus formation, a potential nidus for infection (24, 26, 33). They could circumvent the need for heparin and its potential complications. Rifampin in combination with other lock solutions is synergistic (29, 42). We found that adding rifampin to minocycline and ciprofloxacin produced broad antimicrobial activity; it was antagonistic with vancomycin.

The results of our in vitro study are promising regarding alternative lock solutions that could overcome some of the pitfalls of current agents. MEDTA, T/PVP, C/R, M/R, and E should be considered as lock solutions in large randomized controlled trials.


   ACKNOWLEDGMENTS
 
Disclosure of potential conflict of interest: R.J.S. and I.I.R. are co-patent holders of U.S. patent 5,362,754 for MEDTA (see reference 27).


   FOOTNOTES
 
* Corresponding author. Mailing address: Section on Infectious Diseases, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27517. Phone: (336) 716-4584. Fax: (336) 716-3825. E-mail: sherertz{at}wfubmc.edu. Back


   REFERENCES
Top
 Abstract
 Text
 References
 

  1. Alderson, L., P. Sampath, J. W. Darnowski, and P. Calabresi. 18 Dec 2005, accession date. Phase I/II clinical and pharmacologic studies with taurolidine in patients with recurrent glioblastoma multiforme. Abstracts of the 2001 American Society of Clinical Oncology Annual Meeting, abstr. 2061. [Online.] http://www.asco.org/ac.
  2. Allon, M. 2003. Prophylaxis against dialysis catheter-related bacteremia with a novel antimicrobial lock solution. Clin. Infect. Dis. 36:1539-1544.[CrossRef][Medline]
  3. Anonymous. 10 June 2005, accession date. Ethanol. Micromedex Healthcare Series, vol. 124. Thomson Micromedex, Greenwood Village, Colorado.
  4. Beathard, G. A. 1999. Management of bacteremia associated with tunneled-cuffed hemodialysis catheters. J. Am. Soc. Nephrol. 10:1045-1049.[Abstract/Free Full Text]
  5. Bedrosian, I., R. D. Sofia, S. M. Wolff, and C. A. Dinarello. 1991. Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells. Cytokine 3:568-575.[CrossRef][Medline]
  6. Betjes, M. G., and M. van Agteren. 2004. Prevention of dialysis catheter-related sepsis with a citrate-taurolidine-containing lock solution. Nephrol. Dial. Transplant. 19:1546-1551.[Abstract/Free Full Text]
  7. Bleyer, A., L. Mason, I. Raad, and R. Sherertz. 2000. A randomized, double-blind trial comparing minocycline/EDTA vs heparin as flush solutions for hemodialysis catheters. Infect. Control Hosp. Epidemiol. 21:100-101.
  8. Browne, M. K., G. B. Leslie, and R. W. Pfirrmann. 1976. Taurolin, a new chemotherapeutic agent. J. Appl. Bacteriol. 41:363-368.[Medline]
  9. Capdevila, J. A., A. Segarra, A. M. Planes, M. Ramirez-Arellano, A. Pahissa, L. Piera, and J. M. Martinez-Vazquez. 1993. Successful treatment of haemodialysis catheter-related sepsis without catheter removal. Nephrol. Dial. Transplant. 8:231-234.[Abstract/Free Full Text]
  10. Carratalà, J., J. Niubó, A. Fernández-Sevilla, E. Juvé, X. Castellsagué, J. Berlanga, J. Liñares, and F. Gudiol. 1999. Randomized, double-blind trial of an antibiotic-lock technique for prevention of gram-positive central venous catheter-related infection in neutropenic patients with cancer. Antimicrob. Agents Chemother. 43:2200-2204.[Abstract/Free Full Text]
  11. Chatzinikolaou, I., T. F. Zipf, H. Hanna, J. Umphrey, W. M. Roberts, R. Sherertz, R. Hachem, and I. Raad. 2003. Minocycline-ethylenediaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer. Clin. Infect. Dis. 36:116-119.[CrossRef][Medline]
  12. Christensen, G. D., A. L. Bisno, J. T. Parisi, B. McLaughlin, M. G. Hester, and R. W. Luther. 1982. Nosocomial septicemia due to multiply antibiotic-resistant Staphylococcus epidermidis. Ann. Intern. Med. 96:1-10.[Medline]
  13. Cucarella, C., M. A. Tormo, E. Knecht, B. Amorena, I. Lasa, T. J. Foster, and J. R. Penadés. 2002. Expression of the biofilm-associated protein interferes with host-protein receptors of Staphylococcus aureus and alters the infective process. Infect. Immun. 70:3180-3186.[Abstract/Free Full Text]
  14. Dannenberg, C., U. Bierbach, A. Rothe, J. Beer, and D. Korholz. 2003. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheters. J. Pediatr. Hematol. Oncol. 25:616-621.[CrossRef][Medline]
  15. Fleming, M. S. J. Mihic, and R. A. Harris. 2001. Ethanol, p. 429-445. In J. G. Hardman and L. E. Limbird (ed.), Goodman and Gillman's the pharmacological basis of therapeutics, 3rd ed. McGraw-Hill, New York, N.Y.
  16. Gorman, S. P., D. F. McCafferty, A. D. Woolfson, and D. S. Jones. 1987. A comparative study of the microbial antiadherence capacities of three antimicrobial agents. J. Clin. Pharm. Ther. 12:393-399.[Medline]
  17. Gorman, S. P., D. F. McCafferty, A. D. Wolfson, and D. S. Jones. 1987. Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with taurolin, a novel antimicrobial agent. J. Appl. Bacteriol. 62:315-320.[Medline]
  18. Hampton, A. A., and R. J. Sherertz. 1988. Vascular-access infections in hospitalized patients. Surg. Clin. N. Am. 68:57-71.
  19. Henrickson, K. J., R. A. Axtell, S. M. Hoover, S. M. Kuhn, J. Pritchett, S. C. Kehl, and J. P. Klein. 2000. Prevention of central venous catheter-related infections and the thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: a randomized, multicenter, double-blind trial. J. Clin. Oncol. 18:1269-1278.[Abstract/Free Full Text]
  20. Marr, K. A., D. J. Sexton, P. J. Conlon, G. R. Corey, S. J. Schwab, and K. B. Kirkland. 1997. Catheter-related bacteremia and outcome of attempted catheter salvage in patients undergoing hemodialysis. Ann. Intern. Med. 127:275-280.[Abstract/Free Full Text]
  21. Metcalf, S. C., S. T. Chambers, and A. D. Pithie. 2004. Use of ethanol locks to prevent recurrent central line sepsis. J. Infect. 49:20-22.[CrossRef][Medline]
  22. Pascual, A., E. Ramirez de Arellano, L. Martinez-Martinez, and E. J. Perea. 1993. Effect of polyurethane catheters and bacterial biofilms on the in-vitro activity of antimicrobial agents against Staphylococcus epidermidis. J. Hosp. Infect. 24:211-218.[CrossRef][Medline]
  23. Pennington, C. R., and A. D. Pithie. 1987. Ethanol lock in the management of catheter occlusion. J. Parenter. Enteral Nutr. 11:507-508.[Abstract]
  24. Raad, I. 1998. Intravascular-catheter-related infections. Lancet 351:893-898.[CrossRef][Medline]
  25. Raad, I., A. Buzaid, J. Rhyne, R. Hachem, R. Darouiche, H. Safar, M. Albitar, and R. J. Sherertz. 1997. Minocycline and ethylenediaminetetraacetate for the prevention of recurrent vascular catheter infections. Clin. Infect. Dis. 25:149-151.[Medline]
  26. Raad, I., and G. P. Bodey. 1992. Infectious complications of indwelling vascular catheters. Clin. Infect. Dis. 15:197-208.[Medline]
  27. Raad, I., and R. J. Sherertz. November 1994. M-EDTA pharmaceutical preparations and uses thereof. U.S. patent 5,362,754.
  28. Raad, I., M. Luna, S. A. Khalil, J. W. Costerton, C. Lam, and G. P. Bodey. 1994. The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 271:1014-1016.[Abstract]
  29. Raad, I., R. Darouiche, R. Hachem, M. Sacilowski, and G. P. Bodey. 1995. Antibiotics and prevention of microbial colonization of catheters. Antimicrob. Agents Chemother. 39:2397-2400.[Abstract]
  30. Raad, I., R. Hachem, R. K. Tcholakian, and R. Sherertz. 2002. Efficacy of minocycline and EDTA lock solution in preventing catheter-related bacteremia, septic phlebitis, and endocarditis in rabbits. Antimicrob. Agents Chemother. 46:327-332.[Abstract/Free Full Text]
  31. Radner, D. B. 1973. Toxicologic and pharmacologic aspects of rifampin. Chest 64:213-216.[Abstract/Free Full Text]
  32. Ramirez de Arellano, E., A. Pascual, L. Martinez Martinez, and E. J. Perea. 1994. Activity of eight antibacterial agents on Staphylococcus epidermidis attached to Teflon catheters. J. Med. Microbiol. 40:43-47.[Abstract]
  33. Reinmuller, J. 1999. The influence of taurolidine on physiological and pathological blood coagulation and implications for its use. Zentralbl. Chir. 124:13-18.
  34. Root, J. L., O. R. McIntyre, N. J. Jacobs, and C. P. Daghlian. 1988. Inhibitory effect of disodium EDTA upon the growth of Staphylococcus epidermidis in vitro: relation to infection prophylaxis of Hickman catheters. Antimicrob. Agents Chemother. 32:1627-1631.[Abstract/Free Full Text]
  35. Rubie, H., M. Juricic, S. Claeyssens, A. Krimou, J. Lemozy, P. Izard, J. Guitard, M. Ane, M. F. Prere, and F. Fedacou. 1995. Morbidity using subcutaneous ports and efficacy of vancomycin flushing in cancer. Arch. Dis. Child. 72:325-329.[Abstract]
  36. Rutala, W. A., S. L. Barbee, N. C. Aguiar, M. D. Sobsey, and D. J. Weber. 2000. Antimicrobial activity of home disinfectants and natural products against potential human pathogens. Infect. Control Hosp. Epidemiol. 21:33-38.[CrossRef][Medline]
  37. Schwartz, C., K. J. Henrickson, K. Roghmann, and K. Powell. 1990. Prevention of bacteremia attributed to luminal colonization of tunneled central venous catheters with vancomycin-susceptible organisms. J. Clin. Oncol. 8:1591-1597.[Abstract]
  38. Shah, C. B., M. W. Mittelman, J. W. Costerton, S. Parenteau, M. Pelak, R. Arsenault, and L. A. Mermel. 2002. Antimicrobial activity of a novel catheter lock solution. Antimicrob. Agents Chemother. 46:1674-1679.[Abstract/Free Full Text]
  39. Sherertz, R. J. 2000. Pathogenesis of vascular catheter infections, p. 111-125. In F. A. Waldvogel and A. L. Bisno (ed.), Infections associated with indwelling medical devices, 3rd ed. ASM Press, Washington, D.C.
  40. Simon, C., V. Malerczyk, I. Preuss, K. Schmidt, and H. Grahmann. 1976. Activity in vitro and pharmacokinetics of minocycline. Arzneim.-Forsch. 26:556-560.[Medline]
  41. Sissons, C. H., L. Wong, and T. W. Cutress. 1996. Inhibition by ethanol of the growth of biofilm and dispersed microcosm dental plaques. Arch. Oral Biol. 41:27-34.[CrossRef][Medline]
  42. Sodemann, K., I. Lubrich-Birker, O. Berger, J. Baumert, B. Feldmer, and E. von Hodenberg. 1997. Gentamicin/sodium-citrate mixture as antibiotic-lock technique for salvage and prevention of catheter-related infections—a four-year trial, abstr. A0811. J. Am. Soc. Nephrol. 8:173A.
  43. Tanriover, B., D. Carlton, S. Saddekni, K. Hamrick, R. Oser, A. O. Westfall, and M. Allon. 2000. Bacteremia associated with tunneled dialysis catheters: comparison of two treatment strategies. Kidney Int. 61:2151-2155.
  44. Timsit, J. F., J. C. Farkas, J. M. Boyer, J. B. Martin, B. Misset, B. Renaud, and J. Carlet. 1998. Central vein catheter-related thrombosis in intensive care patients: incidence, risk factors, and relationship with catheter-related sepsis. Chest 114:207-213.[Abstract/Free Full Text]
  45. Torres-Viera, C., C. Thauvin-Eliopoulos, M. Souli, P. DeGirolami, M. G. Farris, C. B. Wennersten, R. D. Sofia, and G. M. Eliopoulos. 2000. Activities of taurolidine in vitro and in experimental enterococcal endocarditis. Antimicrob. Agents Chemother. 44:1720-1724.[Abstract/Free Full Text]
  46. Vance-Bryan, K., R. P. Guay, and J. C. Rotschafer. 1990. Clinical pharmacokinetics of ciprofloxacin. Clin. Pharmacokinet. 19:434-461.[Medline]
  47. Werlin, S. L., T. Lausten, S. Jessen, L. Toy, A. Norton, L. Dallman, J. Bender, L. Sabilan, and D. Rutkowski. 1995. Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. J. Parenter. Enteral Nutr. 19:416-418.[Abstract]
  48. Wilhelm, M. P., and L. Estes. 1999. Symposium on antimicrobial agents—part XII. Vancomycin. Mayo Clin. Proc. 74:928-935.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1865-1868, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1865-1868.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sherertz, R. J.
Right arrow Articles by Raad, I. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sherertz, R. J.
Right arrow Articles by Raad, I. I.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS