Antimicrobial susceptibility studies
Comparative in vitro activities of daptomycin, linezolid, and quinupristin/dalfopristin against Gram-positive bacterial isolates from a large cancer center

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Abstract

Our objective was to evaluate and compare the in vitro activity of daptomycin, linezolid, and quinupristin/dalfopristin against clinical bloodstream isolates of Gram-positive pathogens from a large cancer center in the Northeastern United States. Minimum inhibitory concentrations (MICs) were determined for daptomycin, quinupristin/dalfopristin, and linezolid against 258 isolates; bactericidal activity was evaluated using time-kill experiments against 14 representative pathogens. Vancomycin-resistant enterococci represented the largest proportion of bacteria tested (32% of the isolates), followed by methicillin-resistant coagulase-negative staphylococci (23%), and vancomycin sensitive enterococci (14%). Against staphylococci, the MIC90 was 1 μg/mL for both daptomycin and quinupristin/dalfopristin and 4 μg/mL for linezolid. Against enterococci, the MIC90 for both daptomycin and linezolid was 4 μg/mL and was 16 μg/mL for quinupristin/dalfopristin. The quinupristin/dalfopristin MIC90 for Enterococcus faecium was 2 μg/mL. Two enterococci were linezolid resistant and remained susceptible to daptomycin. In vitro time-kill studies found daptomycin to be rapidly bactericidal against the majority of organisms tested, killing 99.9% of bacteria within 6 h. Quinupristin/dalfopristin was bactericidal against staphylococci and bacteriostatic against most enterococci. Linezolid was bacteriostatic against all organisms evaluated. Daptomycin, quinupristin/dalfopristin, and linezolid each demonstrated in vitro activity against this collection of organisms. Future clinical studies to evaluate a potential role for these agents in the management of infections in cancer patients, including the treatment of febrile neutropenia, appear warranted.

Introduction

A significant increase has been observed in the number of Gram-positive infections over the last 2 decades (Gold and Moellering, 1996). This change has been particularly evident in the cancer population (Pizzo et al., 1978, Pizzo, 1993, Hughes et al., 2002) and is in part a side effect of evolving changes in the clinical care of these patients. Such changes include an increase in the availability and use of indwelling devices, fluoroquinolone prophylaxis, high-dose chemotherapy with hematopoeitic stem cell rescue, and more aggressive use of dose-intense and dose-dense chemotherapeutic regimens.

Superimposed with the increasing prevalence of Gram-positive infections is the problem of resistance. Gram-positive organisms, in addition to becoming more common pathogens, have also developed resistance to many previously effective antibiotics (Gold and Moellering, 1996). The prevalence of methicillin-resistant Staphylococcus aureus is as high as 40%–50% in some centers, in addition to an ever growing concern over the development of vancomycin-resistant S. aureus. Similarly, vancomycin-resistant enterococci have become significant pathogens in the immunocompromised cancer patient population (Hughes et al., 2002). The increasing prevalence of multidrug-resistant Gram-positive pathogens highlights a critical need for newer therapeutic options to treat this growing population of patients.

More recently, several antimicrobials with broad spectrum activity against Gram-positive pathogens have been approved for use in the United States. These agents include quinupristin/dalfopristin, linezolid, and daptomycin. None of these agents have received indications for use in the immunocompromised patient population, and there have been no formal clinical studies evaluating their use in the treatment of febrile neutropenia. Limited clinical data suggest that both quinupristin/dalfopristin and linezolid may be effective for treating resistant infections in the cancer patient with neutropenia (Raad et al., 2001, Smith et al., 2003), and a small head-to-head comparison found these 2 agents to be of comparable efficacy (Raad et al., 2004). Despite similar efficacy, clinical response rates remain poor in this population, suggesting a need for more potent antimicrobials or consideration of combination regimens.

Daptomycin, a recently approved lipopeptide, has demonstrated bactericidal activity against both S. aureus and enterococci, potentially providing some advantages in treating infections in patients with an impaired immune system. The purpose of this study was to evaluate the in vitro activities of linezolid, daptomycin, and quinupristin/dalfopristin against clinical isolates of Gram-positive bacteria in immunocompromised cancer patients at our institution.

Section snippets

Susceptibility testing

Gram-positive blood isolates collected from immunocompromised cancer patients in routine clinical practice were used in this study. Isolates were collected between 1999 and 2003, and 1 isolate per patient was collected to avoid duplicates. Macrobroth dilution minimum inhibitory concentrations (MICs) were performed in accordance with the National Committee of Clinical Laboratory Standards (NCCLS) for the susceptibility testing of bacteria that grow aerobically. To ensure viability, isolates

Susceptibility testing

Macrobroth dilution MICs were determined for a total of 258 clinical isolates. A summary of the isolates tested and corresponding susceptibility results are provided in Table 1. Vancomycin-resistant enterococci represented the largest proportion of bacteria tested (32% of the isolates), followed by methicillin-resistant coagulase-negative staphylococci (23%) and vancomycin-sensitive enterococci (14%). In addition, there were 6 viridans group streptococci isolates evaluated representing only 2%

Discussion

Daptomycin, quinupristin/dalfopristin, and linezolid were each active against this group of Gram-positive isolates collected from cancer patients with bacteremia, including most multidrug-resistant strains. The MIC90 for all staphylococci was within established NCCLS susceptibility breakpoints for all 3 agents and was less than the resistance breakpoint for enterococci. In comparison to linezolid and quinupristin/dalfopristin, daptomycin achieved a more rapid and consistent bactericidal kill

Acknowledgments

The authors are grateful to Robert Botzer for excellent technical assistance. Financial support was provided by Cubist Pharmaceuticals.

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