Infect Chemother.  2011 Aug;43(4):322-338. 10.3947/ic.2011.43.4.322.

Oral Agents for the Treatment of Orthopedic Infections Caused by Methicillin-resistant Staphylococci

• Kim BN

• KMID: 1936069
• DOI: http://doi.org/10.3947/ic.2011.43.4.322

Abstract

Orthopedic infections, especially implant-associated infections, are difficult to treat. Long-term oral antibiotic, along with appropriate surgery, is often needed to eradicate infections. The question still remains which antibiotic regimen is best in this setting because of a paucity of large comparative clinical trials. I reviewed in vitro and in vivo studies evaluating the effectiveness of various oral antibiotic regimens of monotherapy or combination therapy for orthopedic infections caused by methicillin-resistant staphylococci.

Keyword

Antibiotic treatment; Staphylococcus; Osteomyelitis; Infectious arthritis; Orthopedic fixation devices; Joint prosthesis

MeSH Terms

Arthritis, Infectious
Joint Prosthesis
Methicillin Resistance
Orthopedic Fixation Devices
Orthopedics
Osteomyelitis
Staphylococcus

Reference

1. Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004. 364:369–379.

2. Lazzarini L, Mader JT, Calhoun JH. Osteomyelitis in long bones. J Bone Joint Surg Am. 2004. 86-A:2305–2318.

3. Conterno LO, da Silva Filho CR. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev. 2009. CD004439.

4. Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis. 2005. 9:127–138.

5. Stengel D, Bauwens K, Sehouli J, Ekkernkamp A, Porzsolt F. Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infect Dis. 2001. 1:175–188.

6. Frank G, Mahoney HM, Eppes SC. Musculoskeletal infections in children. Pediatr Clin North Am. 2005. 52:1083–1106.

7. Steer AC, Carapetis JR. Acute hematogenous osteomyelitis in children: recognition and management. Paediatr Drugs. 2004. 6:333–346.

8. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004. 351:1645–1654.

9. Gouliouris T, Aliyu SH, Brown NM. Spondylodiscitis: update on diagnosis and management. J Antimicrob Chemother. 2010. 65:Suppl 3. iii11–iii24.

10. Mylona E, Samarkos M, Kakalou E, Fanourgiakis P, Skoutelis A. Pyogenic vertebral osteomyelitis: a systematic review of clinical characteristics. Semin Arthritis Rheum. 2009. 39:10–17.

11. Mathews CJ, Weston VC, Jones A, Field M, Coakley G. Bacterial septic arthritis in adults. Lancet. 2010. 375:846–855.

12. Widmer AF. New developments in diagnosis and treatment of infection in orthopedic implants. Clin Infect Dis. 2001. 33:Suppl 2. S94–S106.

13. Barberán J. Management of infections of osteoarticular prosthesis. Clin Microbiol Infect. 2006. 12:Suppl 3. 93–101.

14. Widmer AF, Frei R, Rajacic Z, Zimmerli W. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis. 1990. 162:96–102.

15. Darley ES, MacGowan AP. Antibiotic treatment of gram-positive bone and joint infections. J Antimicrob Chemother. 2004. 53:928–935.

16. Kenny MT, Strates B. Metabolism and pharmacokinetics of the antibiotic rifampin. Drug Metab Rev. 1981. 12:159–218.

17. Cluzel RA, Lopitaux R, Sirot J, Rampon S. Rifampicin in the treatment of osteoarticular infections due to staphylococci. J Antimicrob Chemother. 1984. 13:Suppl C. 23–29.

18. Rayner C, Munckhof WJ. Antibiotics currently used in the treatment of infections caused by Staphylococcus aureus. Intern Med J. 2005. 35:Suppl 2. S3–S16.

19. O'Neill AJ, Cove JH, Chopra I. Mutation frequencies for resistance to fusidic acid and rifampicin in Staphylococcus aureus. J Antimicrob Chemother. 2001. 47:647–650.

20. Strausbaugh LJ, Jacobson C, Sewell DL, Potter S, Ward TT. Antimicrobial therapy for methicillin-resistant Staphylococcus aureus colonization in residents and staff of a Veterans Affairs nursing home care unit. Infect Control Hosp Epidemiol. 1992. 13:151–159.

21. Kadurugamuwa JL, Sin LV, Yu J, Francis KP, Purchio TF, Contag PR. Noninvasive optical imaging method to evaluate postantibiotic effects on biofilm infection in vivo. Antimicrob Agents Chemother. 2004. 48:2283–2287.

22. Fraimow HS. Systemic antimicrobial therapy in osteomyelitis. Semin Plast Surg. 2009. 23:90–99.

23. Zimmerli W, Frei R, Widmer AF, Rajacic Z. Microbiological tests to predict treatment outcome in experimental device-related infections due to Staphylococcus aureus. J Antimicrob Chemother. 1994. 33:959–967.

24. Lucet JC, Herrmann M, Rohner P, Auckenthaler R, Waldvogel FA, Lew DP. Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1990. 34:2312–2317.

25. Saginur R, Stdenis M, Ferris W, Aaron SD, Chan F, Lee C, Ramotar K. Multiple combination bactericidal testing of staphylococcal biofilms from implant-associated infections. Antimicrob Agents Chemother. 2006. 50:55–61.

26. Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med. 2008. 168:805–819.

27. Drancourt M, Stein A, Argenson JN, Roiron R, Groulier P, Raoult D. Oral treatment of Staphylococcus spp. infected orthopaedic implants with fusidic acid or ofloxacin in combination with rifampicin. J Antimicrob Chemother. 1997. 39:235–240.

28. Drancourt M, Stein A, Argenson JN, Zannier A, Curvale G, Raoult D. Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants. Antimicrob Agents Chemother. 1993. 37:1214–1218.

29. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Foreign-Body Infection (FBI) Study Group. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. JAMA. 1998. 279:1537–1541.

30. Samuel JR, Gould FK. Prosthetic joint infections: single versus combination therapy. J Antimicrob Chemother. 2010. 65:18–23.

31. Howden BP, Grayson ML. Dumb and dumber--the potential waste of a useful antistaphylococcal agent: emerging fusidic acid resistance in Staphylococcus aureus. Clin Infect Dis. 2006. 42:394–400.

32. Collignon P, Turnidge J. Fusidic acid in vitro activity. Int J Antimicrob Agents. 1999. 12:Suppl 2. S45–S58.

33. Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 1999. 12:Suppl 2. S23–S34.

34. Hierholzer G, Rehn J, Knothe H, Masterson J. Antibiotic therapy of chronic post-traumatic osteomyelitis. J Bone Joint Surg Br. 1974. 56-B:721–729.

35. Turnidge J, Collignon P. Resistance to fusidic acid. Int J Antimicrob Agents. 1999. 12:Suppl 2. S35–S44.

36. Turnidge J, Grayson ML. Optimum treatment of staphylococcal infections. Drugs. 1993. 45:353–366.

37. Coombs RR. Fusidic acid in staphylococcal bone and joint infection. J Antimicrob Chemother. 1990. 25:Suppl B. 53–60.

38. Atkins B, Gottlieb T. Fusidic acid in bone and joint infections. Int J Antimicrob Agents. 1999. 12:Suppl 2. S79–S93.

39. Ernst J. Fucidin treatment of chronic staphylococcal osteitis and osteomyelitis. Acta Orthop Scand. 1969. 40:677.

40. Coombs RR, Menday AP. Fusidic acid in orthopaedic infections due to coagulase-negative staphylococci. Curr Med Res Opin. 1985. 9:587–590.

41. Coombs RRH, Mehtar S, Menday AP. Fusidic acid in orthopaedics. Curr Ther Res Clin Exp. 1987. 42:501–508.

42. Murillo O, Doménech A, Garcia A, Tubau F, Cabellos C, Gudiol F, Ariza J. Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2006. 50:4011–4017.

43. Schwank S, Rajacic Z, Zimmerli W, Blaser J. Impact of bacterial biofilm formation on in vitro and in vivo activities of antibiotics. Antimicrob Agents Chemother. 1998. 42:895–898.

44. Rissing JP. Antimicrobial therapy for chronic osteomyelitis in adults: role of the quinolones. Clin Infect Dis. 1997. 25:1327–1333.

45. Jones ME, Critchley IA, Karlowsky JA, Blosser-Middleton RS, Schmitz FJ, Thornsberry C, Sahm DF. In vitro activities of novel nonfluorinated quinolones PGE 9262932 and PGE 9509924 against clinical isolates of Staphylococcus aureus and Streptococcus pneumoniae with defined mutations in DNA gyrase and topoisomerase IV. Antimicrob Agents Chemother. 2002. 46:1651–1657.

46. Metzler K, Hansen GM, Hedlin P, Harding E, Drlica K, Blondeau JM. Comparison of minimal inhibitory and mutant prevention drug concentrations of 4 fluoroquinolones against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus. Int J Antimicrob Agents. 2004. 24:161–167.

47. Turnidge J. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Drugs. 1999. 58:Suppl 2. 29–36.

48. Karamanis EM, Matthaiou DK, Moraitis LI, Falagas ME. Fluoroquinolones versus beta-lactam based regimens for the treatment of osteomyelitis: a meta-analysis of randomized controlled trials. Spine. 2008. 33:E297–E304.

49. Lew DP, Waldvogel FA. Use of quinolones in osteomyelitis and infected orthopaedic prosthesis. Drugs. 1999. 58:Suppl 2. 85–91.

50. Fong IW, Ledbetter WH, Vandenbroucke AC, Simbul M, Rahm V. Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob Agents Chemother. 1986. 29:405–408.

51. Rimmelé T, Boselli E, Breilh D, Djabarouti S, Bel JC, Guyot R, Saux MC, Allaouchiche B. Diffusion of levofloxacin into bone and synovial tissues. J Antimicrob Chemother. 2004. 53:533–535.

52. Dan M, Keynan O, Feldbrin Z, Poch F. Concentrations of moxifloxacin in serum and synovial fluid, and ex vivo bactericidal activity against arthritis-causing pathogens. Diagn Microbiol Infect Dis. 2004. 48:283–286.

53. Metallidis S, Topsis D, Nikolaidis J, Alexiadou E, Lazaraki G, Grovaris L, Theodoridou A, Nikolaidis P. Penetration of moxifloxacin and levofloxacin into cancellous and cortical bone in patients undergoing total hip arthroplasty. J Chemother. 2007. 19:682–687.

54. Metallidis S, Charokopos N, Nikolaidis J, Alexiadou E, Lazaraki G, Koumentaki E, Tsona A, Theodoridis G, Nikolaidis P. Penetration of moxifloxacin into sternal bone of patients undergoing routine cardiopulmonary bypass surgery. Int J Antimicrob Agents. 2006. 28:428–432.

55. Malincarne L, Ghebregzabher M, Moretti MV, Egidi AM, Canovari B, Tavolieri G, Francisci D, Cerulli G, Baldelli F. Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty. J Antimicrob Chemother. 2006. 57:950–954.

56. Blumberg HM, Rimland D, Carroll DJ, Terry P, Wachsmuth IK. Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistant Staphylococcus aureus. J Infect Dis. 1991. 163:1279–1285.

57. Piercy EA, Barbaro D, Luby JP, Mackowiak PA. Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother. 1989. 33:128–130.

58. Vaudaux P, Francois P, Bisognano C, Schrenzel J, Lew DP. Comparison of levofloxacin, alatrofloxacin, and vancomycin for prophylaxis and treatment of experimental foreign-body-associated infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2002. 46:1503–1509.

59. Murillo O, Pachón ME, Euba G, Verdaguer R, Tubau F, Cabellos C, Cabo J, Gudiol F, Ariza J. Antagonistic effect of rifampin on the efficacy of high-dose levofloxacin in staphylococcal experimental foreign-body infection. Antimicrob Agents Chemother. 2008. 52:3681–3686.

60. Kalteis T, Beckmann J, Schröder HJ, Schaumburger J, Linde HJ, Lerch K, Lehn N. Treatment of implant-associated infections with moxifloxacin: an animal study. Int J Antimicrob Agents. 2006. 27:444–448.

61. Kalteis T, Beckmann J, Schröder HJ, Handel M, Grifka J, Lehn N, Lerch K. Moxifloxacin superior to vancomycin for treatment of bone infections--a study in rats. Acta Orthop. 2006. 77:315–319.

62. Murillo O, Pachón ME, Euba G, Verdaguer R, Tubau F, Cabellos C, Cabo J, Gudiol F, Ariza J. High doses of levofloxacin vs moxifloxacin against staphylococcal experimental foreign-body infection: the effect of higher MIC-related pharmacokinetic parameters on efficacy. J Infect. 2009. 58:220–226.

63. Ozturan KE, Yucel I, Kocoglu E, Cakici H, Guven M. Efficacy of moxifloxacin compared to teicoplanin in the treatment of implant-related chronic osteomyelitis in rats. J Orthop Res. 2010. 28:1368–1372.

64. Grossi O, Caillon J, Arvieux C, Jacqueline C, Bugnon D, Potel G, Hamel A. In vivo efficacy of moxifloxacin compared with cloxacillin and vancomycin in a Staphylococcus aureus rabbit arthritis experimental model. Antimicrob Agents Chemother. 2007. 51:3401–3403.

65. Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother. 1990. 34:40–43.

66. Segev S, Yaniv I, Haverstock D, Reinhart H. Safety of long-term therapy with ciprofloxacin: data analysis of controlled clinical trials and review. Clin Infect Dis. 1999. 28:299–308.

67. Greenberg RN, Newman MT, Shariaty S, Pectol RW. Ciprofloxacin, lomefloxacin, or levofloxacin as treatment for chronic osteomyelitis. Antimicrob Agents Chemother. 2000. 44:164–166.

68. Ketterl R, Beckurts T, Stübinger B, Claudi B. Use of ofloxacin in open fractures and in the treatment of post-traumatic osteomyelitis. J Antimicrob Chemother. 1988. 22:Suppl C. 159–166.

69. Dellamonica P, Bernard E, Etesse H, Garraffo R, Drugeon HB. Evaluation of pefloxacin, ofloxacin and ciprofloxacin in the treatment of thirty-nine cases of chronic osteomyelitis. Eur J Clin Microbiol Infect Dis. 1989. 8:1024–1030.

70. San Juan R, Garcia-Reyne A, Caba P, Chaves F, Resines C, Llanos F, López-Medrano F, Lizasoain M, Aguado JM. Safety and efficacy of moxifloxacin monotherapy for treatment of orthopedic implant-related staphylococcal infections. Antimicrob Agents Chemother. 2010. 54:5161–5166.

71. Centers for Disease Control and Prevention (CDC). Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep. 2005. 54:1201–1205.

72. Smilack JD, Flittie WH, Williams TW Jr. Bone concentrations of antimicrobial agents after parenteral administration. Antimicrob Agents Chemother. 1976. 9:169–171.

73. Rodriguez W, Ross S, Khan W, McKay D, Moskowitz P. Clindamycin in the treatment of osteomyelitis in children: a report of 29 cases. Am J Dis Child. 1977. 131:1088–1093.

74. Berger SA, Barza M, Haher J, McFarland JJ, Louie S, Kane A. Penetration of clindamycin into decubitus ulcers. Antimicrob Agents Chemother. 1978. 14:498–499.

75. Landersdorfer CB, Bulitta JB, Kinzig M, Holzgrabe U, Sörgel F. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet. 2009. 48:89–124.

76. Norden CW, Shinners E, Niederriter K. Clindamycin treatment of experimental chronic osteomyelitis due to Staphylococcus aureus. J Infect Dis. 1986. 153:956–959.

77. Levin TP, Suh B, Axelrod P, Truant AL, Fekete T. Potential clindamycin resistance in clindamycin-susceptible, erythromycin-resistant Staphylococcus aureus: report of a clinical failure. Antimicrob Agents Chemother. 2005. 49:1222–1224.

78. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance In vitro. Clin Infect Dis. 2003. 37:1257–1260.

79. Drinkovic D, Fuller ER, Shore KP, Holland DJ, Ellis-Pegler R. Clindamycin treatment of Staphylococcus aureus expressing inducible clindamycin resistance. J Antimicrob Chemother. 2001. 48:315–316.

80. Kaplan SL, Mason EO Jr, Feigin RD. Clindamycin versus nafcillin or methicillin in the treatment of Staphylococcus aureus osteomyelitis in children. South Med J. 1982. 75:138–142.

81. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Joint Working Party of the British Society for Joint Working Party of the British Society for Antimicrobial Chemotherapy. Hospital Infection Society and Infection Control Nurses Association. Guidelines for the prophylaxis and treat-ment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother. 2006. 57:589–608.

82. Xue IB, Davey PG, Phillips G. Variation in postantibiotic effect of clindamycin against clinical isolates of Staphylococcus aureus and implications for dosing of patients with osteomyelitis. Antimicrob Agents Chemother. 1996. 40:1403–1407.

83. Geddes AM, Dwyer NS, Ball AP, Amos RS. Clindamycin in bone and joint infections. J Antimicrob Chemother. 1977. 3:501–507.

84. Pontifex AH, McNaught DR. The treatment of chronic osteomyelitis with clindamycin. Can Med Assoc J. 1973. 109:105–107.

85. Martínez-Aguilar G, Avalos-Mishaan A, Hulten K, Hammerman W, Mason EO Jr, Kaplan SL. Community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J. 2004. 23:701–706.

86. Toma MB, Smith KM, Martin CA, Rapp RP. Pharmacokinetic considerations in the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Orthopedics. 2006. 29:497–501.

87. Grim SA, Rapp RP, Martin CA, Evans ME. Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus. Pharmacotherapy. 2005. 25:253–264.

88. Smilack JD. Trimethoprim-sulfamethoxazole. Mayo Clin Proc. 1999. 74:730–734.

89. Libecco JA, Powell KR. Trimethoprim/sulfamethoxazole: clinical update. Pediatr Rev. 2004. 25:375–380.

90. Masters PA, O'Bryan TA, Zurlo J, Miller DQ, Joshi N. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med. 2003. 163:402–410.

91. Saux MC, Le Rebeller A, Leng B, Mintrosse J. Bone diffusion of trimethoprim and sulfamethoxazole high pressure liquid chromatography (HPLC) (author's transl). Pathol Biol (Paris). 1982. 30:385–388.

92. Sattar MA, Cawley MI, Holt JE, Sankey MG, Kaye CM. The penetration of trimethoprim and sulphamethoxazole into synovial fluid. J Antimicrob Chemother. 1983. 12:229–233.

93. Norden CW, Keleti E. Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination. Antimicrob Agents Chemother. 1980. 17:591–594.

94. Garau J, Bouza E, Chastre J, Gudiol F, Harbarth S. Management of methicillin-resistant Staphylococcus aureus infections. Clin Microbiol Infect. 2009. 15:125–136.

95. Adra M, Lawrence KR. Trimethoprim/sulfamethoxazole for treatment of severe Staphylococcus aureus infections. Ann Pharmacother. 2004. 38:338–341.

96. Craven JL, Pugsley DJ, Blowers R. Trimethoprim-sulphamethoxazole in acute osteomyelitis due to penicillin-resistant staphylococci in Uganda. Br Med J. 1970. 3:201–203.

97. Proctor RA. Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis. 2008. 46:584–593.

98. Bajpai J, Chaturvedi SN, Khanuja SP. Chemotherapy of acute bone and joint infections. Int Surg. 1977. 62:172–174.

99. Yeldandi V, Strodtman R, Lentino JR. In-vitro and in-vivo studies of trimethoprim-sulphamethoxazole against multiple resistant Staphylococcus aureus. J Antimicrob Chemother. 1988. 22:873–880.

100. Stein A, Bataille JF, Drancourt M, Curvale G, Argenson JN, Groulier P, Raoult D. Ambulatory treatment of multidrug-resistant Staphylococcus-infected orthopedic implants with high-dose oral co-trimoxazole (trimethoprim-sulfamethoxazole). Antimicrob Agents Chemother. 1998. 42:3086–3091.

101. Ruhe JJ, Monson T, Bradsher RW, Menon A. Use of long-acting tetracyclines for methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin Infect Dis. 2005. 40:1429–1434.

102. Minuth JN, Holmes TM, Musher DM. Activity of tetracycline, doxycycline, and minocycline against methicillin-susceptible and -resistant staphylococci. Antimicrob Agents Chemother. 1974. 6:411–414.

103. Jonas M, Cunha BA. Minocycline. Ther Drug Monit. 1982. 4:137–145.

104. Dornbusch K. The detection of doxycycline activity in human bone. Scand J Infect Dis Suppl. 1976. 47–53.

105. Gnarpe H, Dornbusch K, Hagg O. Doxycycline concentration levels in bone, soft tissue and serum after intravenous infusion of doxycycline. A clinical study. Scand J Infect Dis Suppl. 1976. 54–57.

106. Preininger RE. Treatment of chronic staphylococcal osteomyelitis with minocycline hydrochloride: a case report. Curr Ther Res Clin Exp. 1973. 15:578–580.

107. Yuk JH, Dignani MC, Harris RL, Bradshaw MW, Williams TW, Jr . Minocycline as an alternative antistaphylococcal agent. Rev Infect Dis. 1991. 13:1023–1024.

108. Dasgupta MK, Shishido H, Salama S, Singh R, Larabie M, Micetich RG. The effects of macrolide and quinolone antibiotics in methicillin-resistant Staphylococcus aureus biofilm growth. Adv Perit Dial. 1997. 13:214–217.

109. Sorensen TS, Colding H, Schroeder E, Rosdahl VT. The penetration of cefazolin, erythromycin and methicillin into human bone tissue. Acta Orthop Scand. 1978. 49:549–553.

110. Grayson ML. Kucers' The Use of Antibiotics. 2010. 6th ed. London: Hodder Arnold;751–769.

111. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother. 1990. 25:Suppl A. 73–82.

112. Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA. Pharmacokinetic and In vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother. 1987. 31:1948–1954.

113. Lode H. The pharmacokinetics of azithromycin and their clinical significance. Eur J Clin Microbiol Infect Dis. 1991. 10:807–812.

114. Malizia T, Batoni G, Ghelardi E, Baschiera F, Graziani F, Blandizzi C, Gabriele M, Campa M, Del Tacca M, Senesi S. Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. J Periodontol. 2001. 72:1151–1156.

115. O'Reilly T, Kunz S, Sande E, Zak O, Sande MA, Tauber MG. Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin. Antimicrob Agents Chemother. 1992. 36:2693–2697.

116. Clemett D, Markham A. Linezolid. Drugs. 2000. 59:815–827. discussion 828.

117. Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. JAMA. 2001. 285:1291.

118. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, Kuter DJ. Hematologic effects of linezolid: Summary of clinical experience. Antimicrob Agents Chemother. 2002. 46:2723–2726.

119. Falagas ME, Siempos II, Papagelopoulos PJ, Vardakas KZ. Linezolid for the treatment of adults with bone and joint infections. Int J Antimicrob Agents. 2007. 29:233–239.

120. Rho JP, Sia IG, Crum BA, Dekutoski MB, Trousdale RT. Linezolid-associated peripheral neuropathy. Mayo Clin Proc. 2004. 79:927–930.

121. Lovering AM, Zhang J, Bannister GC, Lankester BJ, Brown JH, Narendra G, MacGowan AP. Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. J Antimicrob Chemother. 2002. 50:73–77.

122. Rana B, Butcher I, Grigoris P, Murnaghan C, Seaton RA, Tobin CM. Linezolid penetration into osteo-articular tissues. J Antimicrob Chemother. 2002. 50:747–750.

123. Kutscha-Lissberg F, Hebler U, Muhr G, Koller M. Linezolid penetration into bone and joint tissues infected with methicillin-resistant staphylococci. Antimicrob Agents Chemother. 2003. 47:3964–3966.

124. Traunmuller F, Schintler MV, Spendel S, Popovic M, Mauric O, Scharnagl E, Joukhadar C. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections. Int J Antimicrob Agents. 2010. 36:84–86.

125. Grohs P, Kitzis MD, Gutmann L. In vitro bactericidal activities of linezolid in combination with vancomycin, gentamicin, ciprofloxacin, fusidic acid, and rifampin against Staphylococcus aureus. Antimicrob Agents Chemother. 2003. 47:418–420.

126. Jacqueline C, Caillon J, Le Mabecque V, Miegeville AF, Donnio PY, Bugnon D, Potel G. In vitro activity of linezolid alone and in combination with gentamicin, vancomycin or rifampicin against methicillin-resistant Staphylococcus aureus by time-kill curve methods. J Antimicrob Chemother. 2003. 51:857–864.

127. Patel R, Piper KE, Rouse MS, Steckelberg JM. Linezolid therapy of Staphylococcus aureus experimental osteomyelitis. Antimicrob Agents Chemother. 2000. 44:3438–3440.

128. Calhoun JH, Stevens CM, Stevens J, Mader J. Comparative evaluation of vancomycin and linezolid, a novel oxazolidinone, in the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis-studies with a rabbit model. Paper presented at: Annual Meeting of the American Academy of Orthopaedic Surgeons. 2002. February 13-17; Dallas, USA. –42.

129. Vergidis P, Rouse MS, Euba G, Karau MJ, Schmidt SM, Mandrekar JN, Steckelberg JM, Patel R. Treatment with linezolid or vancomycin in combination with rifampin is effective in an animal model of methicillin-resistant Staphylococcus aureus foreign body osteomyelitis. Antimicrob Agents Chemother. 2011. 55:1182–1186.

130. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis. 2003. 36:159–168.

131. Razonable RR, Osmon DR, Steckelberg JM. Linezolid therapy for orthopedic infections. Mayo Clin Proc. 2004. 79:1137–1144.

132. Rayner CR, Baddour LM, Birmingham MC, Norden C, Meagher AK, Schentag JJ. Linezolid in the treatment of osteomyelitis: results of compassionate use experience. Infection. 2004. 32:8–14.

133. Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L, Pipino F, Cruciani M, Bassetti D. Linezolid in the treatment of Gram-positive prosthetic joint infections. J Antimicrob Chemother. 2005. 55:387–390.

134. Aneziokoro CO, Cannon JP, Pachucki CT, Lentino JR. The effectiveness and safety of oral linezolid for the primary and secondary treatment of osteomyelitis. J Chemother. 2005. 17:643–650.

135. Senneville E, Legout L, Valette M, Yazdanpanah Y, Beltrand E, Caillaux M, Migaud H, Mouton Y. Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study. Clin Ther. 2006. 28:1155–1163.

136. Rao N, Hamilton CW. Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series. Diagn Microbiol Infect Dis. 2007. 59:173–179.

137. Lu PL, Wang JT, Chen CJ, Chen WC, Chen TC, Hwang YC, Chang SC. Compassionate use of linezolid for adult Taiwanese patients with bone and joint infections. Chemotherapy. 2010. 56:429–435.

138. Howden BP, Ward PB, Charles PG, Korman TM, Fuller A, du Cros P, Grabsch EA, Roberts SA, Robson J, Read K, Bak N, Hurley J, Johnson PD, Morris AJ, Mayall BC, Grayson ML. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis. 2004. 38:521–528.

139. Ferry T, Uckay I, Vaudaux P, Francois P, Schrenzel J, Harbarth S, Laurent F, Bernard L, Vandenesch F, Etienne J, Hoffmeyer P, Lew D. Risk factors for treatment failure in orthopedic device-related methicillin-resistant Staphylococcus aureus infection. Eur J Clin Microbiol Infect Dis. 2010. 29:171–180.

140. Neu HC. Synergy and antagonism of combinations with quinolones. Eur J Clin Microbiol Infect Dis. 1991. 10:255–261.

141. Kaatz GW, Seo SM, Barriere SL, Albrecht LM, Rybak MJ. Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1989. 33:1184–1187.

142. Roder BL, Gutschik E. In-vitro activity of ciprofloxacin combined with either fusidic acid or rifampicin against Staphylococcus aureus. J Antimicrob Chemother. 1989. 23:347–352.

143. Goldstein EJ, Citron DM, Warren YA, Tyrrell KL, Rybak MJ. Virulence characteristics of community-associated Staphylococcus aureus and In vitro activities of moxifloxacin alone and in combination against community-associated and healthcare-associated meticillin-resistant and -susceptible S. aureus. J Med Microbiol. 2008. 57:452–456.

144. Dworkin R, Modin G, Kunz S, Rich R, Zak O, Sande M. Comparative efficacies of ciprofloxacin, pefloxacin, and vancomycin in combination with rifampin in a rat model of methicillin-resistant Staphylococcus aureus chronic osteomyelitis. Antimicrob Agents Chemother. 1990. 34:1014–1016.

145. Henry NK, Rouse MS, Whitesell AL, McConnell ME, Wilson WR. Treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med. 1987. 82:73–75.

146. Pavoni GL, Giannella M, Falcone M, Scorzolini L, Liberatore M, Carlesimo B, Serra P, Venditti M. Conservative medical therapy of prosthetic joint infections: retrospective analysis of an 8-year experience. Clin Microbiol Infect. 2004. 10:831–837.

147. Berdal JE, Skramm I, Mowinckel P, Gulbrandsen P, Bjornholt JV. Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections. Clin Microbiol Infect. 2005. 11:843–845.

148. Laffer RR, Graber P, Ochsner PE, Zimmerli W. Outcome of prosthetic knee-associated infection: evaluation of 40 consecutive episodes at a single centre. Clin Microbiol Infect. 2006. 12:433–439.

149. Barberán J, Aguilar L, Carroquino G, Gimenez MJ, Sanchez B, Martinez D, Prieto J. Conservative treatment of staphylococcal prosthetic joint infections in elderly patients. Am J Med. 2006. 119:993.e7–993.e10.

150. Barberan J, Aguilar L, Gimenez MJ, Carroquino G, Granizo JJ, Prieto J. Levofloxacin plus rifampicin conservative treatment of 25 early staphylococcal infections of osteosynthetic devices for rigid internal fixation. Int J Antimicrob Agents. 2008. 32:154–157.

151. Soriano A, Garcia S, Bori G, Almela M, Gallart X, Macule F, Sierra J, Martinez JA, Suso S, Mensa J. Treatment of acute post-surgical infection of joint arthroplasty. Clin Microbiol Infect. 2006. 12:930–933.

152. Viale P, Furlanut M, Scudeller L, Pavan F, Negri C, Crapis M, Zamparini E, Zuiani C, Cristini F, Pea F. Treatment of pyogenic (non-tuberculous) spondylodiscitis with tailored high-dose levofloxacin plus rifampicin. Int J Antimicrob Agents. 2009. 33:379–382.

153. Senneville E, Yazdanpanah Y, Cazaubiel M, Cordonnier M, Valette M, Beltrand E, Khazarjian A, Maulin L, Alfandari S, Caillaux M, Dubreuil L, Mouton Y. Rifampicin-ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis. J Antimicrob Chemother. 2001. 48:927–930.

154. Schrenzel J, Harbarth S, Schockmel G, Genne D, Bregenzer T, Flueckiger U, Petignat C, Jacobs F, Francioli P, Zimmerli W, Lew DP. A randomized clinical trial to compare fleroxacin-rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection. Clin Infect Dis. 2004. 39:1285–1292.

155. Frippiat F, Meunier F, Derue G. Place of newer quinolones and rifampicin in the treatment of Gram-positive bone and joint infections. J Antimicrob Chemother. 2004. 54:1158. author reply 9.

156. Drugeon HB, Caillon J, Juvin ME. In-vitro antibacterial activity of fusidic acid alone and in combination with other antibiotics against methicillin-sensitive and -resistant Staphylococcus aureus. J Antimicrob Chemother. 1994. 34:899–907.

157. Cox RA, Mallaghan C, Conquest C, King J. Epidemic methicillin-resistant Staphylococcus aureus: controlling the spread outside hospital. J Hosp Infect. 1995. 29:107–119.

158. Aboltins CA, Page MA, Buising KL, Jenney AW, Daffy JR, Choong PF, Stanley PA. Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid. Clin Microbiol Infect. 2007. 13:586–591.

159. Torda AJ, Gottlieb T, Bradbury R. Pyogenic vertebral osteomyelitis: analysis of 20 cases and review. Clin Infect Dis. 1995. 20:320–328.

160. Donaldson AD, Chan RC, Gosbell IB. Community-acquired methicillin-resistant Staphylococcus aureus in bone and joint infections: development of rifampicin resistance. Med J Aust. 2006. 184:196.

161. Alvarez S, DeMaria A Jr, Kulkarni R, Klein JO, McCabe WR. Interactions of rifampin and trimethoprim In vitro. Rev Infect Dis. 1982. 4:390–401.

162. Kaka AS, Rueda AM, Shelburne SA 3rd, Hulten K, Hamill RJ, Musher DM. Bactericidal activity of orally available agents against methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2006. 58:680–683.

163. Kerry DW, Hamilton-Miller JM, Brumfitt W. Trimethoprim and rifampicin: In vitro activities separately and in combination. J Antimicrob Chemother. 1975. 1:417–427.

164. Harvey RJ. Antagonistic interaction of rifampicin and trimethoprim. J Antimicrob Chemother. 1978. 4:315–327.

165. Gruneberg RN, Emmerson AM. Prevention of emergence of bacterial resistance by combination of two antibiotics: rifampicin and trimethoprim. J Antimicrob Chemother. 1980. 6:349–356.

166. Mandell GL, Moorman DR. Treatment of experimental staphylococcal infections: effect of rifampin alone and in combination on development of rifampin resistance. Antimicrob Agents Chemother. 1980. 17:658–662.

167. Zander J, Besier S, Ackermann H, Wichelhaus TA. Synergistic antimicrobial activities of folic acid antagonists and nucleoside analogs. Antimicrob Agents Chemother. 2010. 54:1226–1231.

168. Zander J, Besier S, Faetke S, Saum SH, Muller V, Wichelhaus TA. Antimicrobial activities of trimethoprim/sulfamethoxazole, 5-iodo-2'-deoxyuridine and rifampicin against Staphylococcus aureus. Int J Antimicrob Agents. 2010. 36:562–565.

169. Segreti J, Nelson JA, Trenholme GM. Prolonged suppressive antibiotic therapy for infected orthopedic prostheses. Clin Infect Dis. 1998. 27:711–713.

170. Euba G, Murillo O, Fernandez-Sabe N, Mascaro J, Cabo J, Perez A, Tubau F, Verdaguer R, Gudiol F, Ariza J. Long-term follow-up trial of oral rifampin-cotrimoxazole combination versus intravenous cloxacillin in treatment of chronic staphylococcal osteomyelitis. Antimicrob Agents Chemother. 2009. 53:2672–2676.

171. Nguyen S, Pasquet A, Legout L, Beltrand E, Dubreuil L, Migaud H, Yazdanpanah Y, Senneville E. Efficacy and tolerance of rifampicin-linezolid compared with rifampicin-cotrimoxazole combinations in prolonged oral therapy for bone and joint infections. Clin Microbiol Infect. 2009. 15:1163–1169.

172. Zimmerli W, Ochsner PE. Management of infection associated with prosthetic joints. Infection. 2003. 31:99–108.

173. Grimprel E, Lorrot M, Haas H, Pinquier D, Parez N, Ferroni A, Cohen R. Paediatric Infectious Diseases Group of the French Society of Paediatricis (GPIP). Osteoarticular infections: therapeutic proposals of the Paediatric Infectious Diseases Group of the French Society of Paediatrics (GPIP). Arch Pediatr. 2008. 15:Suppl 2. S74–S80.

174. Watanakunakorn C. Effects of clindamycin in combination with rifampicin on clindamycin-susceptible and clindamycin-resistant Staphylococcus aureus. J Antimicrob Chemother. 1985. 16:335–339.

175. Arditi M, Yogev R. In vitro interaction between rifampin and clindamycin against pathogenic coagulase-negative staphylococci. Antimicrob Agents Chemother. 1989. 33:245–247.

176. Rybak MJ, McGrath BJ. Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician. Drugs. 1996. 52:390–405.

177. Monzon M, Oteiza C, Leiva J, Amorena B. Synergy of different antibiotic combinations in biofilms of Staphylococcus epidermidis. J Antimicrob Chemother. 2001. 48:793–801.

178. Segreti J, Gvazdinskas LC, Trenholme GM. In vitro activity of minocycline and rifampin against staphylococci. Diagn Microbiol Infect Dis. 1989. 12:253–255.

179. Yourassowsky E, van der Linden MP, Lismont MJ, Crokaert F. Combination of minocycline and rifampicin against methicillin-and gentamicin-resistant Staphylococcus aureus. J Clin Pathol. 1981. 34:559–563.

180. Isiklar ZU, Darouiche RO, Landon GC, Beck T. Efficacy of antibiotics alone for orthopaedic device related infections. Clin Orthop Relat Res. 1996. 184–189.

181. Haas DW, McAndrew MP. Bacterial osteomyelitis in adults: evolving considerations in diagnosis and treatment. Am J Med. 1996. 101:550–561.

182. Calhoun JH, Stevens CM, Stevens J, Mader J. Comparative evaluation of vancomycin and linezolid, a novel oxazolidinone, in the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis-studies with a rabbit model. Paper presented at: Annual Meeting of the American Academy of Orthopaedic Surgeons. 2002. February 13-17; Dallas, USA. –42.

183. Norden CW, Fierer J, Bryant RE. Chronic staphylococcal osteomyelitis: treatment with regimens containing rifampin. Rev Infect Dis. 1983. 5:Suppl 3. S495–S501.

184. Littlewood-Evans AJ, Hattenberger M, Zak O, O'Reilly T. Effect of combination therapy of rifampicin and azithromycin on TNF levels during a rat model of chronic osteomyelitis. J Antimicrob Chemother. 1997. 39:493–498.

185. Shirtliff ME, Mader JT, Calhoun J. Oral rifampin plus azithromycin or clarithromycin to treat osteomyelitis in rabbits. Clin Orthop Relat Res. 1999. 229–236.

186. Murillo O, Domenech A, Euba G, Verdaguer R, Tubau F, Cabo J, Cabellos C, Gudiol F, Ariza J. Efficacy of linezolid alone and in combination with rifampin in staphylococcal experimental foreign-body infection. J Infect. 2008. 57:229–235.

187. Baldoni D, Haschke M, Rajacic Z, Zimmerli W, Trampuz A. Linezolid alone or combined with rifampin against methicillin-resistant Staphylococcus aureus in experimental foreign-body infection. Antimicrob Agents Chemother. 2009. 53:1142–1148.

188. Legout L, Valette M, Dezeque H, Nguyen S, Lemaire X, Loiez C, Caillaux M, Beltrand E, Dubreuil L, Yazdanpanah Y, Migaud H, Senneville E. Tolerability of prolonged linezolid therapy in bone and joint infection: protective effect of rifampicin on the occurrence of anaemia? J Antimicrob Chemother. 2010. 65:2224–2230.

189. Soriano A, Ortega M, Garcia S, Penarroja G, Bove A, Marcos M, Martinez JC, Martinez JA, Mensa J. Comparative study of the effects of pyridoxine, rifampin, and renal function on hematological adverse events induced by linezolid. Antimicrob Agents Chemother. 2007. 51:2559–2563.

190. Leonard SN, Kaatz GW, Rucker LR, Rybak MJ. Synergy between gemifloxacin and trimethoprim/sulfamethoxazole against community-associated methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2008. 62:1305–1310.

191. Reynaud AE, Espaze EP, Coste-Burel M, Richet H. In vitro kinetics of the activity of fusidic acid and fluoroquinolones combinations against staphylococci according to methicillin-resistance phenotype. Implications for the treatment of osteoarticular infections. Pathol Biol (Paris). 1992. 40:466–470.

192. Ertek M, Yazgi H, Erol S, Altoparlak U. Demonstration of In vitro antagonism between fusidic acid and quinolones. J Int Med Res. 2002. 30:525–528.

193. Learmonth ID, Dall G, Pollock DJ. Acute osteomyelitis and septic arthritis in children. A simple approach to treatment. S Afr Med J. 1984. 65:117–120.

194. Jones NS, Anderson DJ, Stiles PJ. Osteomyelitis in a general hospital. A five-year study showing an increase in subacute osteomyelitis. J Bone Joint Surg Br. 1987. 69:779–783.

195. Humble MW. Imported methicillin-resistant Staphylococcus aureus infection: a case report. N Z Med J. 1976. 84:476–478.