Increased Killing of Staphylococci and Streptococciby Daptomycin Compared with Cefazolin and Vancomycin in an InVitro Peritoneal DialysateModel

Abstract

Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.Roughly 15% (ϳ20,000 to 30,000) of patients with end stage renal disease (ESRD) in the United States are managed with peritoneal dialysis (PD). This number is increasing by nearly 6,000 patients per year and is expected to increase even further in the face of increased economic pressure due to the lower cost of PD relative to hemodialysis (ϳ$32,000 versus $44,000/ year) (18). Moreover, PD allows greater patient freedom and spares the body from large hemodynamic fluctuations when compared with hemodialysis (18).The problem with PD has been, and continues to be, PDassociated peritonitis (PDAP). PDAP accounts for approximately 30 to 40% of all patient transfers to hemodialysis, represents the leading cause for hospitalization among patients on PD, and imposes a significant burden of morbidity and mortality (5, 6). Furthermore, several investigative groups have provided evidence suggesting that repeated or severe episodes of peritonitis may cause the peritoneal membrane to become unsuitable for dialysis, leading to technique failure, requiring either transfer to hemodialysis or transplantation to maintain life (4,7,13,14).The pathogens most commonly associated with peritonitis are gram positive. Approximately 28 to 32% of infections are caused by Staphylococcus epidermidis, 23 to 26% are caused by Staphylococcus aureus, and 20% are caused by other grampositive species (5). Present empirical therapy for peritonitis typically includes administration of a cephalosporin, usually cefazolin, mixed in the peritoneal dialysate fluid (PDF). Vancomycin is used in the setting of known or suspected betalactam resistance (8). However, the bacteriostatic nature of PDF may compromise the antibacterial activity of such cell wall-active agents (2, 10-12, 15, 19, 21).Daptomycin is a novel cyclic lipopeptide antibiotic with rapid, bactericidal activity against gram-positive pathogens (16). Daptomycin is under clinical investigation for...

Characterization of High-Level Daptomycin Resistance in Viridans Group Streptococci Developed upon In Vitro Exposure to Daptomycin

“…In vitro studies evaluating the activity of DAP against various streptococci, including VGS, have shown significant kill without development of resistance. There is only a single report for an in vitro peritoneal dialysate model where DAP at 10 mg/liter against Streptococcus sanguis (S. sanguinis) displayed more static activity with only a 2-log 10 CFU reduction compared to Ͼ3 log 10 CFU reduction with cefazolin and VAN (42). In addition to reduced activity of DAP, regrowth occurred in the model by 24 h with the authors attributing this to the possibility of inadequate calcium supplementation within the growth media despite noting that the calcium concentration was greater than 50 mg/liter.…”

Bactericidal Action of Daptomycin against Stationary-Phase and Nondividing Staphylococcus aureus Cells

“…Daptomycin is a cyclic lipopeptide antibacterial agent that exhibits rapid, concentration-dependent in vitro bactericidal activity against clinically significant strains of gram-positive pathogens, including streptococci, methicillin-resistant S. aureus, and vancomycin-resistant enterococci (5,13,18,31). In the present study, the observed bactericidal activity against stationary-phase S. aureus ATCC 29213 is remarkable since most other bactericidal agents interfere with cell division or on May 10, 2018 by guest http://aac.asm.org/ processes necessary for cell division and typically have little activity against nondividing cells (30).…”

“…Daptomycin is a lipopeptide antibiotic that displays rapid bactericidal activity in vitro against gram-positive pathogens, including streptococci, methicillin-resistant S. aureus, and vancomycin-resistant enterococci (5,13,18,31). Daptomycin works by disrupting membrane function and causing leakage of essential potassium ions, ultimately leading to loss of membrane potential and cell death (26).…”

Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

“…However, the relatively poor pharmacodynamic effects of both these drugs compared to those of the fluoroquinolones might have resulted in a lower eradication efficacy due to the slower bactericidal action of vancomycin and the bacteriostatic effect of linezolid (6,12). The superior pharmacokinetic advantages of vancomycin and linezolid are reflected by the lower protective doses that we found in the mouse protection studies (survival with linezolid treatment; data not shown).…”