- Email: [email protected]
Current and new antimicrobial agents
Current and new antimicrobial agents George M. Eliopoulos, MD Boston, Mass
Background
Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics.
Methods
The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci.
Results
The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed.
Conclusions Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents. (Am Heart J 2004;147:587–92.) Infection may arise as a complication of cardiovascular surgery. Alternatively, infection of cardiovascular structures may require surgery for optimal management. In either case, antibiotic therapy directed at the causative pathogens will almost always be required. This paper will review the clinical use of older antibiotics and provide an overview of the properties of 2 more recently approved agents and of 2 compounds still being clinically investigated.
Bacteria Gram-positive bacteria are major etiologic agents of infections encountered in cardiovascular surgery. Staphylococcus aureus is a major cause of endovascular infection and may complicate surgical procedures by causing wound infections, infections of implanted devices, catheter-associated sepsis, and processes at other sites.1– 6 Coagulase-negative staphylococci are infrequently implicated in primary infection of normal From the Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass. Based on a presentation to the National Institutes of Health working group, Antibacterial Strategies in Cardiovascular Surgery, Bethesda, Md, April 4 –5, 2002. The author has served as a consultant for and received research contracts from Aventis Pharmaceuticals, Cubist Pharmaceuticals, and Pfizer, Inc, and has served as a consultant for Virucon Pharmaceuticals. Submitted January 28, 2003; accepted June 19, 2003. Published online March 5, 2004. Reprint requests: George M. Eliopoulos, MD, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.06.006
heart values, but are well known to cause infection of implanted devices, including prosthetic heart valves.2,4,7–9 These organisms can cause postoperative infections, and lead to bacteremia that can result in secondary seeding of endovascular structures. Viridans streptococci are commonly isolated when patients have native valve bacterial endocarditis, a setting in which enterococci also cause infection.1,2 Although a broad range of gram-negative organisms and some fungi or other organisms can also complicate cardiovascular surgery, the emphasis of this discussion will be on agents that target gram-positive bacteria, in particular staphylococci.
Challenge of increasing antibiotic resistance Two decades ago, the overwhelming majority of S aureus isolates were susceptible to anti-staphylococcal penicillins and cephalosporins, drugs that typically both inhibited and killed these organisms. This situation has changed considerably. Recent surveys of organisms collected in US clinical laboratories indicate that approximately one third of S aureus isolates are now oxacillin-resistant strains.10 These are more commonly still referred to as “methicillin-resistant S aureus” or MRSA. These organisms account for ⬎50% of S aureus strains causing nosocomial infections in intensive care units. Often, these hospital-associated MRSA strains are resistant to a variety of other antimicrobial agents, including fluoroquinolones, macrolides, and clindamycin.11 MRSA are considered to be resistant to all currently available beta-lactam antibiotics.12
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Most hospital-associated isolates of Staphylococcus epidermidis are also resistant to anti-staphylococcal betalactams. Although most strains of oxacillin-resistant staphylococci also produce beta-lactamase, this resistance to beta-lactams in S aureus and in coagulasenegative staphylococci is ascribed to the presence of a low-affinity penicillin-binding protein, PBP2’ mediated by the mecA gene, which can function even in the presence of high concentrations of beta-lactamasestable beta-lactams.13 More recently, strains of S aureus with reduced susceptibility to vancomycin have been recognized in the United States and abroad.14 Such isolates are inhibited by vancomycin concentrations of 8 to 16 g/mL, which falls into the range of intermediate susceptibility by National Committee for Clinical Laboratory Standards (NCCLS) criteria.12 However, infections caused by these “vancomycin-intermediate S aureus” have not responded well to vancomycin.15,16 At present, only a handful of true vancomycin-intermediate S aureus isolates (which were also MRSA) have been encountered in the United States.14,16 The mechanisms of resistance have not been completely defined, but appear to involve non-productive binding of vancomycin to a thickened, poorly cross-linked cell wall.17,18 In 2002, 2 isolates of MRSA were encountered in the United States that were fully resistant to vancomycin, with minimum inhibitory concentrations of 32 to 64 g/mL and ⬎1000 g/mL. Vancomycin resistance in these isolates arose by yet another mechanism: acquisition of the vanA genes, which cause vancomycin resistance in enterococci.19,20 It is important to stress that these are the only such isolates reported to date, and therefore represent a very rare occurrence.
Previously available antibiotics The anti-staphylococcal (penicillinase-stable) penicillins have been, and continue to be, extremely valuable agents for treatment of serious infections caused by oxacillin-susceptible strains of S aureus. When tested in vitro, these agents often demonstrate bactericidal activity against S aureus. Combinations of such penicillins with an aminoglycoside may synergistically enhance the degree of staphylococcal killing achievable in vitro.21 In the classic study of Korzeniowski and Sande,22 the combination of nafcillin (6 weeks) and gentamicin (2 weeks) was compared with nafcillin alone (6 weeks) for the treatment of S aureus endocarditis in patients who used parenteral drugs and in patients who were not addicts. Although the combination resulted in more rapid defervescence in the former group and a shorter duration of blood culture positivity in the latter population, these benefits came at the cost of some nephrotoxicity. The combination did not enhance survival or diminish valve damage.
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Therefore, for treatment of native valve oxacillin-susceptible S aureus endocarditis, if the combination is used at all, a common approach has been to limit aminoglycoside therapy to 3 to 5 days, while giving a several week course of the anti-staphylococcal penicillin,23 in an attempt to exploit the potential for enhanced early killing while minimizing risks of toxicity. There are no clear data, however, on which to judge the relative value of this approach. There are some limitations to the use of anti-staphylococcal beta-lactams. Unfortunately, some patients cannot tolerate drugs of this class because of allergy or other difficulties. Some of these patients can tolerate cephalosporin therapy, but others cannot. The pharmacokinetic characteristics of these beta-lactams also require parenteral administration. A major limitation, however, has been the emergence of MRSA as an increasingly frequent pathogen. For patients with serious infections caused by MRSA, or in patients with infections caused by oxacillin-susceptible organisms who are intolerant of beta-lactam antibiotics, vancomycin is usually used. Levine et al24 randomized 42 patients with MRSA endocarditis to treatment with vancomycin alone or vancomycin with rifampin. Most patients had right-sided valve infections. There was no difference in the median days of fever (7 days in both groups) or of positive blood cultures (7 days vs 9 days, respectively) in the 2 groups. Although some patients experience adverse effects from vancomycin, this antibiotic is reasonably well tolerated by most people. The twice-daily regimen that is prescribed for most patients is often more convenient than the more frequent dosing usually required with beta-lactam therapy. However, in vitro, vancomycin tends to kill more slowly than the anti-staphylococcal penicillins.25 In the 2 studies of endocarditis aforementioned,22,24 the duration of MRSA bacteremia in patients treated with vancomycin (median, 7 days) was longer than the duration of MSSA bacteremia in patients treated with nafcillin (median, 3– 4 days). It would be unfair to draw definitive conclusions from a direct comparison of the antimicrobial agents from these different studies. However, there is a general sense that anti-staphylococcal penicillins are preferred to vancomycin for the treatment of serious S aureus infections in patients with susceptible organisms who can tolerate drugs of either class.26
Recently approved agents with activity against staphylococci Because some patients are intolerant of both betalactam and glycopeptide antimicrobial agents, and because of increasing concerns about the potential emergence of antibiotic resistance aforementioned, the approval of 2 new antimicrobial agents, in 1999 and
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2000, provided additional options for therapy of grampositive infections. The general characteristics of these agents have been summarized previously,27 and an update was provided in a recent commentary.28 The following is intended as a brief overview to illustrate the properties of the newest antimicrobial agents. Practitioners should refer to official documentation or obtain expert consultation for specific recommendations regarding their use.
Quinupristin-dalfopristin Representatives of the streptogramin A and streptogramin B families of antibiotics occur naturally in combinations that synergistically achieve levels of activity superior to those provided by either antibiotic alone. Quinupristin-dalfopristin, is produced from such a natural product (quinupristin is a streptogramin B and dalfopristin is a streptogramin A), yielding a water-soluble drug suitable for intravenous administration.27 Its mechanism of action involves inhibition of protein synthesis. In the United States, the overwhelming majority (⬎99%) of S aureus, including both MRSA and oxacillin-susceptible strains, would be expected to be susceptible to this agent in vitro.29 Very high rates of susceptibility to quinupristin-dalfopristin were also found for coagulase-negative staphylococcal species. The combination is potentially bactericidal against isolates susceptible to both components. Against isolates with constitutive resistance to the macrolide-lincosamidestreptogramin B (MLSB) class of antibiotics, which is seen frequently in MRSA and less commonly among oxacillin-susceptible S aureus,11 the combination loses bactericidal activity in vitro.30 This is because such isolates are resistant to quinupristin, which is a streptogramin B antibiotic. As long as strains remain susceptible to dalfopristin, however, the combination retains inhibitory activity. In the United States, the only Food and Drug Administration-approved use31 of quinupristin-dalfopristin as an anti-staphylococcal agent is for treatment of adults with complicated skin and skin structure infections when the pathogen is an oxacillin-susceptible S aureus. Otherwise, the drug is approved for complicated skin and skin structure infections caused by Streptococcus pyogenes and for serious vancomycin-resistant Enterococcus faecium infections associated with bacteremia (the drug is not active against Enterococcus faecalis). Quinupristin-dalfopristin is only available for intravenous administration, and the formulation is not compatible with saline. Because this antibiotic is very irritating when given by peripheral vein, a deep catheter is usually required. A syndrome of arthralgias and myalgias, which may become very severe, will develop in many patients treated with this combination.32 This syndrome has been reversible with the discontinuation of treatment. Administration of quinupristin-dalfopris-
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tin can interfere with clearance of drugs that are eliminated through the cytochrome P450 system, so care is required to avoid potentially serious drug-drug interactions.31
Linezolid This agent is the first member of the oxazolidinone series to be approved as an antimicrobial agent for clinical use. Linezolid has a broad spectrum of activity against gram-positive organisms, including staphylococci, streptococci, and enterococci. Essentially all strains of S aureus, including MRSA, from clinical surveys are inhibited by this agent at or lower than the susceptibility breakpoint of 4 g/mL.29 To date, there are 2 published reports of clinical isolates of S aureus resistant to linezolid on the basis of mutations in 23S ribosomal RNA, in an area central to peptide bond formation.33,34 Similar mutations, leading to linezolid resistance, have also been encountered among enterococcal strains.35 The action of linezolid against S aureus is best described as bacteriostatic, although some killing can occur slowly with time.25 A major advantage of this agent is that it is available both for intravenous and oral use. The Food and Drug Administration-approved indications for linezolid use are relatively broad.36 They include (but are not limited to) complicated skin and skin structure infections caused by MRSA or oxacillinsusceptible S aureus or group A or B streptococci, S aureus nosocomial pneumonia, and infections caused by vancomycin-resistant enterococci. When linezolid was compared with vancomycin in an open-label, randomized study of MRSA infections, the clinical and microbiological outcomes were equivalent.37 With compassionate use protocols, linezolid has been used successfully in many patients who did not respond to treatment with vancomycin or who were intolerant of the latter antibiotic.38 However, patients with MRSA endocarditis who experience failure in attempts at treatment with linezolid have also been reported,39 and the oxazolidinone is not approved for this indication. Linezolid has the potential to cause myelosuppression.36 Although all cell lines may be affected,40 the greatest attention has focused on thrombocytopenia. In comparative clinical trials, there was a small, and not statistically significant, increase in occurrence of substantially low platelet counts in patients treated with linezolid (2.4% vs 1.5%), which generally became apparent after approximately 2 weeks of therapy.41 However, in some case series, low platelet counts were observed in ⱖ20% of patients receiving the drug.42,43 Recommendations for monitoring blood counts are included in the package insert for this agent.36 Linezolid is a weak monoamine oxidase inhibitor,27 and serotonin syndrome has been reported
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rarely in patients who had also received a selective serotonin reuptake inhibitor.44
Drugs being clinically investigated Several agents with in vitro antimicrobial activity against staphylococci have been studied in clinical trials. Daptomycin was approved by the US Food and Drug Administration in September 2003. The other 2 agents discussed herein are not approved for use in the United States at present.
Daptomycin This agent is a cyclic lipopeptide antibiotic, which is derived from a natural product structurally unrelated to other currently available antibiotics.45 The drug exhibits a calcium-dependent antimicrobial effect against staphylococci, including MRSA.46 The spectrum includes vancomycin-intermediate S aureus, coagulasenegative staphylococcal species, and many other grampositive bacteria.46,47 The drug’s activity is typically bactericidal against staphylococi.25 The antimicrobial activity of daptomycin appears to result from disruption of cell membrane function.45 Initial clinical studies with this agent were begun in the 1980s, but development was halted. At a time of increasing concern about the rates of resistance to other antimicrobial agents, development of daptomycin resumed in the late 1990s. The drug has the potential to cause a reversible myopathy; this became evident when high doses were given twice daily. Myopathy appears to be an infrequent event with new dosing regimens.45 Preliminary reports describing phase III study results of complicated skin and skin structure infections indicate that daptomycin produced equivalent rates of clinical success to those seen with standard comparison agents—an anti-staphylococcal penicillin or vancomycin (Roditi D, Arbeit RD, The 99-01 Investigators. Clinical significance of dual infection with Staphylococcus aureus and hemolytic streptococci in complicated skin and soft tissue infections: results from daptomycin trial 99-01. Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill, 2001, abstract no. L-1482).
Oritavancin This agent is a glycopeptide antibiotic derived semisynthetically from a precursor drug closely related to vancomycin. It has activity in vitro against staphylococci, including MRSA, which is generally comparable with that of vancomycin.48,49 In 1 survey that included 283 isolates of oxacillin-susceptible S aureus and 310 strains of MRSA, 90% of isolates in each group were inhibited by this agent at concentrations ⱕ2 g/mL.48 A striking difference in in vitro activity between this agent and vancomycin is that oritavancin can inhibit
vancomycin-resistant enterococci, including strains with vancomycin minimum inhibitory concentrations ⬎1000 g/mL, at concentrations of approximately 1.0 g/mL.48 Oritavancin is bactericidal against S aureus, including MRSA.48 Another major difference between the new glycopeptide and vancomycin is that the elimination half-life of oritavancin is much longer, in the range of 5 to 15 days.50 A preliminary report suggests efficacy of oritavancin in a phase III study of complicated skin and skin structure infections. Oritavancin administered intravenously for 3 to 7 days was compared with vancomycin, also given for 3 to 7 days, followed by oral cephalexin. Rates of clinical success were equivalent for all patients and also for the subset of patients with MRSA infections (Wasilewski MM, Disch DP, McGill JM, et al. Equivalence of shorter course therapy with oritavancin vs. vancomycin/ cephlexin in complicated skin/skin structure infections. Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill, 2001, abstract no. UL-18).
Dalbavancin Dalbavancin is another semi-synthetic glycopeptide antibiotic that is being clinically investigated. This agent is as much as 16-fold more active than vancomycin against staphylococci tested in vitro.51 Like oritavancin, dalbavancin is eliminated slowly from the serum, with a half-life of several days, even in individuals with normal renal function. The developmental program for this agent has exploited this pharmacokinetic feature to advantage, with once-weekly dosing strategies having been used in phase II studies of complicated skin and skin structure infections.52 (Eliopoulos GM. Newer glycopeptides and derivatives. Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif, 2002, abstract no. 1179.)
Summary The older anti-staphylococcal agents remain very useful antibiotics. The usefulness of the beta-lactams has been compromised by the increasing prominence of methicillin-resistant S aureus and coagulase-negative staphylococci, particularly in hospital-associated infections. Vancomycin is still the most widely used antibiotic for treating infections caused by MRSA and methicillin-resistant coagulase-negative staphylococci. At present, vancomycin-intermediate S aureus are rare. For patients with S aureus infections in whom vancomycin doesn’t work or who are intolerant of older therapeutic agents, linezolid or quinupristin-dalfopristin (the latter approved only for oxacillin-susceptible strains) may be useful in the appropriate clinical settings. Presently, clinical studies of sufficient size to
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assess comprehensively the effectiveness of these agents in endovascular infections, and in infections associated with cardiovascular surgery specifically, are lacking. The investigational agents aforementioned offer potential advantages for future use. At present, the newer agents have not been proven to be superior to the older antibiotics for serious staphylococcal infections caused by strains susceptible to both.
References 1. Cabell CH, Abrutyn E. Progress toward a global understanding of infective endocarditis. Early lessons from the International Collaboration on Endocarditis investigation. Infect Dis Clin North Am 2002;16:255–72. 2. Miro´ JM, del Rio A, Mestres CA. Infective endocarditis in intravenous drug abusers and HIV-1 infected patients. Infect Dis Clin North Am 2002;16:273–95. 3. Camus C, Leport C, Raffi F, et al. Sustained bacteremia in 26 patients with permanent endocardial pacemaker: assessment of wire removal. Clin Infect Dis 1993;17:46 –55. 4. Kearney RA, Eisen HJ, Wolf JE. Nonvalvular infections of the cardiovascular system. Ann Intern Med 1994;121:219 –30. 5. Malanoski GJ, Samore MH, Pefanis A, et al. Staphylococcus aureus catheter-associated bacteremia. Arch Intern Med 1995;155: 1161– 6. 6. Petti CA, Fowler VG. Staphylococcus aureus bacteremia and endocarditis. Infect Dis Clin North Am 2002;16:413–35. 7. Gordon SM, Schmitt SK, Jacobs M, et al. Nosocomial bloodstream infections in patients with implantable left ventricular assist devices. Ann Thorac Surg 2001;72:725–30. 8. Douglas JL, Cobbs CG. Prosthetic valve endocarditis. In: Kaye D, editor. Infective endocarditis. 2nd ed. New York: Raven Press; 1992. p. 375–96. 9. Karchmer AW, Longworth DL. Infections of intracardiac devices. Infect Dis Clin North Am 2002;16:477–505. 10. Diekema DJ, Pfaller MA, Schmitz FJ, et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001;32(2 Suppl):S114 –32. 11. Fluit AC, Wielders CL, Verhoef J, et al. Epidemiology and susceptibility of 3051 Staphylococcus aureus isolates from 25 university hospitals participating in the European SENTRY study. J Clin Microbiol 2001;39:3727–32. 12. NCCLS. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement. Wayne (Pa): NCCLS; 2002. p. 96. 13. Quintiliani R, Sahm DF, Courvalin P. Mechanisms of resistance to antimicrobial agents. In: Murray PF, Baron EJ, Pfaller MA, et al, editors. Manual of clinical microbiology. 7th edition. Washington, DC: American Society for Microbiology; 1999. p. 1505–25. 14. Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis 2001;7:327–32. 15. Andrade-Baiocchi S, Tognim MCB, Baiocchi OCG, et al. Endocarditis due to glycopeptide-intermediate Staphylococcus aureus: case report and strain characterization. Diagn Microbiol Infect Dis 2003;45:149 –52.
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16. Fridkin SK, Hageman J, McDougal LK, et al. Epidemiological and microbiological characterization of infections caused by Staphylococcus aureus with reduced susceptibility to vancomycin, United States, 1997–2001. Clin Infect Dis 2003;36:429 – 39. 17. Sieradzki K, Roberts RB, Haber SW, et al. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999;340:517– 23. 18. Finan JE, Archer GL, Climo MW. Role of penicillin-binding protein 4 in expression of vancomycin resistance among clinical isolates of oxacillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2001;45:3070 –5. 19. CDC. Staphylococcus aureus resistant to vancomycin—United States, 2002. Mor Mortal Wkly Rep CDC Surveill Summ 2002;51: 565–7. 20. CDC. Vancomycin-resistant Staphylococcus aureus—Pennsylvania, 2002. Morb Mortal Wkly Rep 2002;51:902. 21. Watanakunakorn C, Glotzbecker C. Enhancement of the effects of anti-staphylococcal antibiotics by aminoglycosides. Antimicrob Agents Chemother 1974;6:802– 6. 22. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med 1982;97:496 –503. 23. Gilbert DN, Moellering RC Jr, Sande MA, editors. The Sanford guide to antimicrobial therapy. Hyde Park, Vt: Antimicrobial Therapy, Inc; 2002. 24. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991;115:674 – 80. 25. Fuchs PC, Barry AL, Brown SD. In vitro bactericidal therapy of daptomycin against staphylococci. J Antimicrob Chemother 2002; 49:467–70. 26. Turnidge J, Chang F-Y, Fowler VG, et al. Staphylococcus aureus. In: Yu VL, Weber R, Raoult D, editors. Antimicrobial therapy and vaccines. 2nd ed. Volume I: microbes. New York: Apple Tree Productions; 2002. p.631–58. 27. Batts DH, Lavin BS, Eliopoulos GM. Quinupristin/dalfopristin and linezolid: spectrum of activity and potential roles in therapy—a status report. Curr Clin Top Infect Dis 2001;21:227–51. 28. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003;36:473⫺81. 29. Ballow CH, Jones RN, Biedenbach DJ, et al. A multicenter evaluation of linezolid antimicrobial activity in North America. Diag Microbiol Infect Dis 2002;43:75– 83. 30. Fuchs PC, Barry AL, Brown SD. Bactericidal activity of quinupristindalfopristin against Staphylococcus aureus: clindamycin susceptibility as a surrogate indicator. Antimicrob Agents Chemother 2000;44:2880 –2. 31. Quinupristin-dalfopristin (Synercid) package literature. Bridgewater (NJ): Aventis Pharmaceutical Products; 2000. 32. Olsen KM, Rebuck JA, Rupp ME. Arthralgias and myalgias related to quinupristin-dalfopristin administration. Clin Infect Dis 2001;32: e83– 6. 33. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001;358: 207– 8. 34. Wilson P, Andrews JA, Charlesworth R, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 2003;51:186 – 8.
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35. Gonzales RD, Schreckenberger PC, Graham MB, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001;357:1179. 36. Linezolid (Zyvox) package literature. Kalamazoo (Mich): Pharmacia & Upjohn Corporation; 2001. 37. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002;34:1481–90. 38. Moise PA, Forrest A, Birmingham MC, et al. The efficacy and safety of linezolid as treatment for Staphylococcus aureus infections in compassionate use patients who are intolerant of, or who have failed to respond to, vancomycin. J Antimicrob Chemother 2002;50:1017–26. 39. Ruiz ME, Guerrero IC, Tuazon CU. Endocarditis caused by methicillin-resistant Staphylococcus aureus: treatment failure with linezolid. Clin Infect Dis 2002;35:1018 –20. 40. Halpern M. Linezolid-induced pancytopenia. Clin Infect Dis 2002; 35:347– 8. 41. Gerson SL, Kaplan SL, Bruss JB, et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 2002;46:2723– 6. 42. Orrick JJ, Johns T, Janelle J, et al. Thrombocytopenia secondary to linezolid administration: what is the risk? Clin Infect Dis 2002;35: 348 –9. 43. Attassi K, Hershberger E, Alam R, et al. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002;34:695– 8. 44. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002;34:1651–2.
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45. Tally FP, DeBruin MF. Development of daptomycin for gram-positive infections. J Antimicrob Chemother 2000;46:523– 6. 46. Petersen PJ, Bradford PA, Weiss WJ, et al. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrob Agents Chemother 2002;46:2595– 601. 47. Barry AL, Fuchs PC, Brown SD. In vitro activities of daptomycin against 2789 clinical isolates from 11 North American medical centers. Antimicrob Agents Chemother 2001;45:1919 –22. 48. Zeckel ML, Preston DA, Allen BS. In vitro activities of LY333328 and comparative agents against nosocomial gram-positive pathogens collected in a 1997 global surveillance study. Antimicrob Agents Chemother 2000;44:1370 – 4. 49. Schwalbe RS, McIntosh AC, Qaiyumi S, et al. In vitro activity of LY333328, an investigational glycopeptide antibiotic, against enterococci and staphylococci. Antimicrob Agents Chemother 1996; 40:2416 –9. 50. Barrett JF. Oritavancin: Eli Lilly & Co. Curr Opin Invest Drugs 2001;2:1039 – 44. 51. Candiani G, Abbondi M, Borgonovi M, et al. In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother 1999;44:179 –92. 52. Selzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis 2003;37:1298 – 303.
Background
Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics.
Methods
The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci.
Results
The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed.
Conclusions Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents. (Am Heart J 2004;147:587–92.) Infection may arise as a complication of cardiovascular surgery. Alternatively, infection of cardiovascular structures may require surgery for optimal management. In either case, antibiotic therapy directed at the causative pathogens will almost always be required. This paper will review the clinical use of older antibiotics and provide an overview of the properties of 2 more recently approved agents and of 2 compounds still being clinically investigated.
Bacteria Gram-positive bacteria are major etiologic agents of infections encountered in cardiovascular surgery. Staphylococcus aureus is a major cause of endovascular infection and may complicate surgical procedures by causing wound infections, infections of implanted devices, catheter-associated sepsis, and processes at other sites.1– 6 Coagulase-negative staphylococci are infrequently implicated in primary infection of normal From the Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass. Based on a presentation to the National Institutes of Health working group, Antibacterial Strategies in Cardiovascular Surgery, Bethesda, Md, April 4 –5, 2002. The author has served as a consultant for and received research contracts from Aventis Pharmaceuticals, Cubist Pharmaceuticals, and Pfizer, Inc, and has served as a consultant for Virucon Pharmaceuticals. Submitted January 28, 2003; accepted June 19, 2003. Published online March 5, 2004. Reprint requests: George M. Eliopoulos, MD, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.06.006
heart values, but are well known to cause infection of implanted devices, including prosthetic heart valves.2,4,7–9 These organisms can cause postoperative infections, and lead to bacteremia that can result in secondary seeding of endovascular structures. Viridans streptococci are commonly isolated when patients have native valve bacterial endocarditis, a setting in which enterococci also cause infection.1,2 Although a broad range of gram-negative organisms and some fungi or other organisms can also complicate cardiovascular surgery, the emphasis of this discussion will be on agents that target gram-positive bacteria, in particular staphylococci.
Challenge of increasing antibiotic resistance Two decades ago, the overwhelming majority of S aureus isolates were susceptible to anti-staphylococcal penicillins and cephalosporins, drugs that typically both inhibited and killed these organisms. This situation has changed considerably. Recent surveys of organisms collected in US clinical laboratories indicate that approximately one third of S aureus isolates are now oxacillin-resistant strains.10 These are more commonly still referred to as “methicillin-resistant S aureus” or MRSA. These organisms account for ⬎50% of S aureus strains causing nosocomial infections in intensive care units. Often, these hospital-associated MRSA strains are resistant to a variety of other antimicrobial agents, including fluoroquinolones, macrolides, and clindamycin.11 MRSA are considered to be resistant to all currently available beta-lactam antibiotics.12
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Most hospital-associated isolates of Staphylococcus epidermidis are also resistant to anti-staphylococcal betalactams. Although most strains of oxacillin-resistant staphylococci also produce beta-lactamase, this resistance to beta-lactams in S aureus and in coagulasenegative staphylococci is ascribed to the presence of a low-affinity penicillin-binding protein, PBP2’ mediated by the mecA gene, which can function even in the presence of high concentrations of beta-lactamasestable beta-lactams.13 More recently, strains of S aureus with reduced susceptibility to vancomycin have been recognized in the United States and abroad.14 Such isolates are inhibited by vancomycin concentrations of 8 to 16 g/mL, which falls into the range of intermediate susceptibility by National Committee for Clinical Laboratory Standards (NCCLS) criteria.12 However, infections caused by these “vancomycin-intermediate S aureus” have not responded well to vancomycin.15,16 At present, only a handful of true vancomycin-intermediate S aureus isolates (which were also MRSA) have been encountered in the United States.14,16 The mechanisms of resistance have not been completely defined, but appear to involve non-productive binding of vancomycin to a thickened, poorly cross-linked cell wall.17,18 In 2002, 2 isolates of MRSA were encountered in the United States that were fully resistant to vancomycin, with minimum inhibitory concentrations of 32 to 64 g/mL and ⬎1000 g/mL. Vancomycin resistance in these isolates arose by yet another mechanism: acquisition of the vanA genes, which cause vancomycin resistance in enterococci.19,20 It is important to stress that these are the only such isolates reported to date, and therefore represent a very rare occurrence.
Previously available antibiotics The anti-staphylococcal (penicillinase-stable) penicillins have been, and continue to be, extremely valuable agents for treatment of serious infections caused by oxacillin-susceptible strains of S aureus. When tested in vitro, these agents often demonstrate bactericidal activity against S aureus. Combinations of such penicillins with an aminoglycoside may synergistically enhance the degree of staphylococcal killing achievable in vitro.21 In the classic study of Korzeniowski and Sande,22 the combination of nafcillin (6 weeks) and gentamicin (2 weeks) was compared with nafcillin alone (6 weeks) for the treatment of S aureus endocarditis in patients who used parenteral drugs and in patients who were not addicts. Although the combination resulted in more rapid defervescence in the former group and a shorter duration of blood culture positivity in the latter population, these benefits came at the cost of some nephrotoxicity. The combination did not enhance survival or diminish valve damage.
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Therefore, for treatment of native valve oxacillin-susceptible S aureus endocarditis, if the combination is used at all, a common approach has been to limit aminoglycoside therapy to 3 to 5 days, while giving a several week course of the anti-staphylococcal penicillin,23 in an attempt to exploit the potential for enhanced early killing while minimizing risks of toxicity. There are no clear data, however, on which to judge the relative value of this approach. There are some limitations to the use of anti-staphylococcal beta-lactams. Unfortunately, some patients cannot tolerate drugs of this class because of allergy or other difficulties. Some of these patients can tolerate cephalosporin therapy, but others cannot. The pharmacokinetic characteristics of these beta-lactams also require parenteral administration. A major limitation, however, has been the emergence of MRSA as an increasingly frequent pathogen. For patients with serious infections caused by MRSA, or in patients with infections caused by oxacillin-susceptible organisms who are intolerant of beta-lactam antibiotics, vancomycin is usually used. Levine et al24 randomized 42 patients with MRSA endocarditis to treatment with vancomycin alone or vancomycin with rifampin. Most patients had right-sided valve infections. There was no difference in the median days of fever (7 days in both groups) or of positive blood cultures (7 days vs 9 days, respectively) in the 2 groups. Although some patients experience adverse effects from vancomycin, this antibiotic is reasonably well tolerated by most people. The twice-daily regimen that is prescribed for most patients is often more convenient than the more frequent dosing usually required with beta-lactam therapy. However, in vitro, vancomycin tends to kill more slowly than the anti-staphylococcal penicillins.25 In the 2 studies of endocarditis aforementioned,22,24 the duration of MRSA bacteremia in patients treated with vancomycin (median, 7 days) was longer than the duration of MSSA bacteremia in patients treated with nafcillin (median, 3– 4 days). It would be unfair to draw definitive conclusions from a direct comparison of the antimicrobial agents from these different studies. However, there is a general sense that anti-staphylococcal penicillins are preferred to vancomycin for the treatment of serious S aureus infections in patients with susceptible organisms who can tolerate drugs of either class.26
Recently approved agents with activity against staphylococci Because some patients are intolerant of both betalactam and glycopeptide antimicrobial agents, and because of increasing concerns about the potential emergence of antibiotic resistance aforementioned, the approval of 2 new antimicrobial agents, in 1999 and
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2000, provided additional options for therapy of grampositive infections. The general characteristics of these agents have been summarized previously,27 and an update was provided in a recent commentary.28 The following is intended as a brief overview to illustrate the properties of the newest antimicrobial agents. Practitioners should refer to official documentation or obtain expert consultation for specific recommendations regarding their use.
Quinupristin-dalfopristin Representatives of the streptogramin A and streptogramin B families of antibiotics occur naturally in combinations that synergistically achieve levels of activity superior to those provided by either antibiotic alone. Quinupristin-dalfopristin, is produced from such a natural product (quinupristin is a streptogramin B and dalfopristin is a streptogramin A), yielding a water-soluble drug suitable for intravenous administration.27 Its mechanism of action involves inhibition of protein synthesis. In the United States, the overwhelming majority (⬎99%) of S aureus, including both MRSA and oxacillin-susceptible strains, would be expected to be susceptible to this agent in vitro.29 Very high rates of susceptibility to quinupristin-dalfopristin were also found for coagulase-negative staphylococcal species. The combination is potentially bactericidal against isolates susceptible to both components. Against isolates with constitutive resistance to the macrolide-lincosamidestreptogramin B (MLSB) class of antibiotics, which is seen frequently in MRSA and less commonly among oxacillin-susceptible S aureus,11 the combination loses bactericidal activity in vitro.30 This is because such isolates are resistant to quinupristin, which is a streptogramin B antibiotic. As long as strains remain susceptible to dalfopristin, however, the combination retains inhibitory activity. In the United States, the only Food and Drug Administration-approved use31 of quinupristin-dalfopristin as an anti-staphylococcal agent is for treatment of adults with complicated skin and skin structure infections when the pathogen is an oxacillin-susceptible S aureus. Otherwise, the drug is approved for complicated skin and skin structure infections caused by Streptococcus pyogenes and for serious vancomycin-resistant Enterococcus faecium infections associated with bacteremia (the drug is not active against Enterococcus faecalis). Quinupristin-dalfopristin is only available for intravenous administration, and the formulation is not compatible with saline. Because this antibiotic is very irritating when given by peripheral vein, a deep catheter is usually required. A syndrome of arthralgias and myalgias, which may become very severe, will develop in many patients treated with this combination.32 This syndrome has been reversible with the discontinuation of treatment. Administration of quinupristin-dalfopris-
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tin can interfere with clearance of drugs that are eliminated through the cytochrome P450 system, so care is required to avoid potentially serious drug-drug interactions.31
Linezolid This agent is the first member of the oxazolidinone series to be approved as an antimicrobial agent for clinical use. Linezolid has a broad spectrum of activity against gram-positive organisms, including staphylococci, streptococci, and enterococci. Essentially all strains of S aureus, including MRSA, from clinical surveys are inhibited by this agent at or lower than the susceptibility breakpoint of 4 g/mL.29 To date, there are 2 published reports of clinical isolates of S aureus resistant to linezolid on the basis of mutations in 23S ribosomal RNA, in an area central to peptide bond formation.33,34 Similar mutations, leading to linezolid resistance, have also been encountered among enterococcal strains.35 The action of linezolid against S aureus is best described as bacteriostatic, although some killing can occur slowly with time.25 A major advantage of this agent is that it is available both for intravenous and oral use. The Food and Drug Administration-approved indications for linezolid use are relatively broad.36 They include (but are not limited to) complicated skin and skin structure infections caused by MRSA or oxacillinsusceptible S aureus or group A or B streptococci, S aureus nosocomial pneumonia, and infections caused by vancomycin-resistant enterococci. When linezolid was compared with vancomycin in an open-label, randomized study of MRSA infections, the clinical and microbiological outcomes were equivalent.37 With compassionate use protocols, linezolid has been used successfully in many patients who did not respond to treatment with vancomycin or who were intolerant of the latter antibiotic.38 However, patients with MRSA endocarditis who experience failure in attempts at treatment with linezolid have also been reported,39 and the oxazolidinone is not approved for this indication. Linezolid has the potential to cause myelosuppression.36 Although all cell lines may be affected,40 the greatest attention has focused on thrombocytopenia. In comparative clinical trials, there was a small, and not statistically significant, increase in occurrence of substantially low platelet counts in patients treated with linezolid (2.4% vs 1.5%), which generally became apparent after approximately 2 weeks of therapy.41 However, in some case series, low platelet counts were observed in ⱖ20% of patients receiving the drug.42,43 Recommendations for monitoring blood counts are included in the package insert for this agent.36 Linezolid is a weak monoamine oxidase inhibitor,27 and serotonin syndrome has been reported
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rarely in patients who had also received a selective serotonin reuptake inhibitor.44
Drugs being clinically investigated Several agents with in vitro antimicrobial activity against staphylococci have been studied in clinical trials. Daptomycin was approved by the US Food and Drug Administration in September 2003. The other 2 agents discussed herein are not approved for use in the United States at present.
Daptomycin This agent is a cyclic lipopeptide antibiotic, which is derived from a natural product structurally unrelated to other currently available antibiotics.45 The drug exhibits a calcium-dependent antimicrobial effect against staphylococci, including MRSA.46 The spectrum includes vancomycin-intermediate S aureus, coagulasenegative staphylococcal species, and many other grampositive bacteria.46,47 The drug’s activity is typically bactericidal against staphylococi.25 The antimicrobial activity of daptomycin appears to result from disruption of cell membrane function.45 Initial clinical studies with this agent were begun in the 1980s, but development was halted. At a time of increasing concern about the rates of resistance to other antimicrobial agents, development of daptomycin resumed in the late 1990s. The drug has the potential to cause a reversible myopathy; this became evident when high doses were given twice daily. Myopathy appears to be an infrequent event with new dosing regimens.45 Preliminary reports describing phase III study results of complicated skin and skin structure infections indicate that daptomycin produced equivalent rates of clinical success to those seen with standard comparison agents—an anti-staphylococcal penicillin or vancomycin (Roditi D, Arbeit RD, The 99-01 Investigators. Clinical significance of dual infection with Staphylococcus aureus and hemolytic streptococci in complicated skin and soft tissue infections: results from daptomycin trial 99-01. Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill, 2001, abstract no. L-1482).
Oritavancin This agent is a glycopeptide antibiotic derived semisynthetically from a precursor drug closely related to vancomycin. It has activity in vitro against staphylococci, including MRSA, which is generally comparable with that of vancomycin.48,49 In 1 survey that included 283 isolates of oxacillin-susceptible S aureus and 310 strains of MRSA, 90% of isolates in each group were inhibited by this agent at concentrations ⱕ2 g/mL.48 A striking difference in in vitro activity between this agent and vancomycin is that oritavancin can inhibit
vancomycin-resistant enterococci, including strains with vancomycin minimum inhibitory concentrations ⬎1000 g/mL, at concentrations of approximately 1.0 g/mL.48 Oritavancin is bactericidal against S aureus, including MRSA.48 Another major difference between the new glycopeptide and vancomycin is that the elimination half-life of oritavancin is much longer, in the range of 5 to 15 days.50 A preliminary report suggests efficacy of oritavancin in a phase III study of complicated skin and skin structure infections. Oritavancin administered intravenously for 3 to 7 days was compared with vancomycin, also given for 3 to 7 days, followed by oral cephalexin. Rates of clinical success were equivalent for all patients and also for the subset of patients with MRSA infections (Wasilewski MM, Disch DP, McGill JM, et al. Equivalence of shorter course therapy with oritavancin vs. vancomycin/ cephlexin in complicated skin/skin structure infections. Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill, 2001, abstract no. UL-18).
Dalbavancin Dalbavancin is another semi-synthetic glycopeptide antibiotic that is being clinically investigated. This agent is as much as 16-fold more active than vancomycin against staphylococci tested in vitro.51 Like oritavancin, dalbavancin is eliminated slowly from the serum, with a half-life of several days, even in individuals with normal renal function. The developmental program for this agent has exploited this pharmacokinetic feature to advantage, with once-weekly dosing strategies having been used in phase II studies of complicated skin and skin structure infections.52 (Eliopoulos GM. Newer glycopeptides and derivatives. Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif, 2002, abstract no. 1179.)
Summary The older anti-staphylococcal agents remain very useful antibiotics. The usefulness of the beta-lactams has been compromised by the increasing prominence of methicillin-resistant S aureus and coagulase-negative staphylococci, particularly in hospital-associated infections. Vancomycin is still the most widely used antibiotic for treating infections caused by MRSA and methicillin-resistant coagulase-negative staphylococci. At present, vancomycin-intermediate S aureus are rare. For patients with S aureus infections in whom vancomycin doesn’t work or who are intolerant of older therapeutic agents, linezolid or quinupristin-dalfopristin (the latter approved only for oxacillin-susceptible strains) may be useful in the appropriate clinical settings. Presently, clinical studies of sufficient size to
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assess comprehensively the effectiveness of these agents in endovascular infections, and in infections associated with cardiovascular surgery specifically, are lacking. The investigational agents aforementioned offer potential advantages for future use. At present, the newer agents have not been proven to be superior to the older antibiotics for serious staphylococcal infections caused by strains susceptible to both.
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45. Tally FP, DeBruin MF. Development of daptomycin for gram-positive infections. J Antimicrob Chemother 2000;46:523– 6. 46. Petersen PJ, Bradford PA, Weiss WJ, et al. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrob Agents Chemother 2002;46:2595– 601. 47. Barry AL, Fuchs PC, Brown SD. In vitro activities of daptomycin against 2789 clinical isolates from 11 North American medical centers. Antimicrob Agents Chemother 2001;45:1919 –22. 48. Zeckel ML, Preston DA, Allen BS. In vitro activities of LY333328 and comparative agents against nosocomial gram-positive pathogens collected in a 1997 global surveillance study. Antimicrob Agents Chemother 2000;44:1370 – 4. 49. Schwalbe RS, McIntosh AC, Qaiyumi S, et al. In vitro activity of LY333328, an investigational glycopeptide antibiotic, against enterococci and staphylococci. Antimicrob Agents Chemother 1996; 40:2416 –9. 50. Barrett JF. Oritavancin: Eli Lilly & Co. Curr Opin Invest Drugs 2001;2:1039 – 44. 51. Candiani G, Abbondi M, Borgonovi M, et al. In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother 1999;44:179 –92. 52. Selzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis 2003;37:1298 – 303.