|
|
In vitro and animal studies of antibiotic synergy for newer antistaphylococcal agents for Staphylococcus aureus
Masashi Narita, M.D.
Invasive Staphylococcus aureus infections are often refractory to antibiotic monotherapy (especially vancomycin). So, combination therapy is often employed. Moreover, many experienced clinicians use combination therapy from outset in severely-ill patients for invasive S. aureus infection. We performed a literature review of the newer antistaphylococcal antibiotics in which synergy was assessed in vitro or in animal studies (Table 1). Methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and heterogeneous glycopeptide-intermediate Staphylococcus aureus (hGISA) were studied. For in vitro studies, time-kill methods, checkerboard methods and E-tests were used. The definition of synergy was the fractional inhibitory concentration index (FICI) < 0.5 in checkerboard method, and reduction >2 log10 CFU/ml in time-kill studies. Three different combinations of antimicrobials showed synergistic interaction against Staphylococcus aureus by two different investigative groups: • Daptomycin plus gentamicin (4,21) • Quinupristin/dalfopristin plus vancomycin (12, 22) • Quinupristin/dalfopristin plus rifampin (7, 20) In one study, the triple combination of daptomycin, gentamicin and rifampin was superior to monotherapy (p<0.01) for MRSA in a cell model as well as agar dilution testing (2). Several regimen employing linezolid showed evidence of synergy in vitro: Linezolid plus fosfomycin (18), linezolid plus ertapenem (8), and linezolid plus imipenem (10) also showed synergistic interaction in vitro against S. aureus. Linezolid plus rifampin (9), and levofloxacin plus rifampin (13) showed synergistic interaction; however, in other studies, these same combinations were found to be indifferent (5). Rifampin is an antibiotic that may play a special role for S. aureus infections. It has superb intracellular penetration and is also highly active against S. aureus. Rifampin was synergistic in vitro with quinupristin as mentioned above with linezolid in one study (9), with levofloxacin in one study (13) and as part of a triple combination of daptomycin plus gentamicin (2). Tigecycline is unique among MRSA antibiotics in that it possesses activity against the enteric gram-negative bacilli and anaerobes. Synergy was found for tigecycline plus gentamicin, and indifference for tigecycline plus rifampin and tigecycline plus vancomycin. Whether synergistic interactions in vitro or in animal models translate into clinical success remains to be determined. Nevertheless, these in vitro results may be of interest for clinicians treating selected patients who have failed standard antibiotic therapy.
TABLE Table 1: In vitro/animal Synergy Studies for Staphylococcus aureus
REFERENCES 1. Allen GP, Cha R, Rybak MJ. In vitro activities of quinupristin-dalfopristin and cefepime, alone and in combination with various antimicrobials, against multidrug-resistant staphylococci and enterococci in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 2002; 46:2606-12. [PubMed] 2. Baltch AL, Ritz WJ, Bopp LH, Michelsen PB, Smith RP. Antimicrobial activities of daptomycin, vancomycin, and oxacillin in human monocytes and of daptomycin in combination with gentamicin and/or rifampin in human monocytes and in broth against Staphylococcus aureus. Antimicrob Agents Chemother 2007; 51:1559-62.[PubMed] 3. Chiang FY, Climo M. Efficacy of linezolid alone or in combination with vancomycin for treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47:3002-4. [PubMed] 4. Credito K, Lin G, Appelbaum PC. Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology. Antimicrob Agents Chemother 2007; 51:1504-7. [PubMed] 5. Dailey CF, Pagano PJ, Buchanan LV, Paquette JA, Haas JV, Gibson JK. Efficacy of linezolid plus rifampin in an experimental model of methicillin-susceptible Staphylococcus aureus endocarditis. Antimicrob Agents Chemother 2003; 47:2655-8. [PubMed] 6. 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; 47:418-20. [PubMed] 7. Hamel A, Caillon J, Jacqueline C, Batard E, Potel G. Efficacy of quinupristin/dalfopristin versus vancomycin, alone or in combination with rifampicin, against methicillin-resistant Staphylococcus aureus in a rabbit arthritis model. Int J Antimicrob Agents 2008; 31:158-60.[PubMed] 8. Jacqueline C, Caillon J, Grossi O, et al. In vitro and in vivo assessment of linezolid combined with ertapenem: a highly synergistic combination against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2006; 50:2547-9. [PubMed] 9. Jacqueline C, Caillon J, Le Mabecque V, et al. 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; 51:857-64. [PubMed] 10. Jacqueline C, Navas D, Batard E, et al. In vitro and in vivo synergistic activities of linezolid combined with subinhibitory concentrations of imipenem against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005; 49:45-51. [PubMed] 11. Kang SL, Rybak MJ. Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model. Antimicrob Agents Chemother 1995; 39:1505-11. [PubMed] 12. Kang SL, Rybak MJ. In-vitro bactericidal activity of quinupristin/dalfopristin alone and in combination against resistant strains of Enterococcus species and Staphylococcus aureus. J Antimicrob Chemother 1997; 39 Suppl A:33-9. [PubMed] 13. Kang SL, Rybak MJ, McGrath BJ, Kaatz GW, Seo SM. Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model. Antimicrob Agents Chemother 1994; 38:2702-9. [PubMed] 14. LaPlante KL, Rybak MJ. Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 2004; 48:4665-72. [PubMed] 15. Mercier RC, Kennedy C, Meadows C. Antimicrobial activity of tigecycline (GAR-936) against Enterococcus faecium and Staphylococcus aureus used alone and in combination. Pharmacotherapy 2002; 22:1517-23. [PubMed] 16. Palmer SM, Rybak MJ. Pharmacodynamics of once- or twice-daily levofloxacin versus vancomycin, with or without rifampin, against Staphylococcus aureus in an in vitro model with infected platelet-fibrin clots. Antimicrob Agents Chemother 1996; 40:701-5. [PubMed] 17. Petersen PJ, Labthavikul P, Jones CH, Bradford PA. In vitro antibacterial activities of tigecycline in combination with other antimicrobial agents determined by chequerboard and time-kill kinetic analysis. J Antimicrob Chemother 2006; 57:573-6. [PubMed] 18. Sahuquillo Arce JM, Colombo Gainza E, Gil Brusola A, Ortiz Estevez R, Canton E, Gobernado M. In vitro activity of linezolid in combination with doxycycline, fosfomycin, levofloxacin, rifampicin and vancomycin against methicillin-susceptible Staphylococcus aureus. Rev Esp Quimioter 2006; 19:252-7. [PubMed] 19. Sakoulas G, Eliopoulos GM, Alder J, Eliopoulos CT. Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47:1714-8. [PubMed] 20. Sambatakou H, Giamarellos-Bourboulis EJ, Grecka P, Chryssouli Z, Giamarellou H. In-vitro activity and killing effect of quinupristin/dalfopristin (RP59500) on nosocomial Staphylococcus aureus and interactions with rifampicin and ciprofloxacin against methicillin-resistant isolates. J Antimicrob Chemother 1998; 41:349-55. [PubMed] 21. Snydman DR, McDermott LA, Jacobus NV. Evaluation of in vitro interaction of daptomycin with gentamicin or beta-lactam antibiotics against Staphylococcus aureus and Enterococci by FIC index and timed-kill curves. J Chemother 2005; 17:614-21. [PubMed] 22. Tsuji BT, Rybak MJ. Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 2005; 49:2735-45. [PubMed] 23. Tsuji BT, Rybak MJ. Etest synergy testing of clinical isolates of Staphylococcus aureus demonstrating heterogeneous resistance to vancomycin. Diagn Microbiol Infect Dis 2006; 54:73-7. [PubMed] 24. Zarrouk V, Bozdogan B, Leclercq R, et al. Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics. Antimicrob Agents Chemother 2001; 45:1244-8. [PubMed] |
|