Abstract
Recent surveillance from US hospitals shows that more than 99.5% of vancomycin-resistant enterococci (VRE) isolates remain susceptible to daptomycin. This report describes emergence of daptomycin-resistant VRE at a major cancer center. The percentage of patients with daptomycin-resistant VRE bacteremia increased from 3.4% in 2007 to 15.2% in 2009 (P = .03). Without susceptibility data, empiric daptomycin therapy for VRE infections should be used with caution.
Vancomycin-resistant enterococci (VRE) were first isolated in the United States in the late 1980s and have spread widely in the ensuing years. The most recent National Nosocomial Infection Surveillance (NNIS) report showed that 28.5% of all enterococcal isolates are resistant to vancomycin.1 Studies have shown poorer clinical outcomes among patients with VRE infections when compared with those infected with vancomycin-susceptible enterococci.2
In the past decade, 4 new drugs with activity against VRE have been licensed for use: quinupristin-dalfopristin (1999), linezolid (2000), tigecycline (2005), and daptomycin (2003). Few studies have examined and compared the efficacy of these agents for use in the treatment of VRE infections. Among the newer drugs, common adverse effects such as myelotoxicity (linezolid) and myalgias (quinupristin-dalfopristin) limit the use in certain circumstances, especially among patients undergoing treatment for cancer.
Recent surveillance studies from US hospitals have demonstrated that more than 99.5% of VRE isolates remain susceptible to daptomycin.3 The purpose of this report is to describe the recent emergence at our hospital of daptomycin-resistant VRE strains.
METHODS
We examined the daptomycin susceptibility profile of all isolates collected during episodes of VRE bacteremia at Memorial Sloan-Kettering Cancer Center (MSKCC) from January 1, 2007, through December 31, 2009.
MSKCC is a 465-bed cancer center in New York City. Routine VRE surveillance is performed in the transplant and intensive care units. Information on all persons colonized or infected with VRE was obtained from the infection control database. Data on the use of daptomycin were obtained from the institutional pharmacy database. Clinical information was retrieved from electronic medical records. The MSKCC Institutional Review Board reviewed the study and granted a Health Insurance Portability and Accountability Act waiver of authorization.
Laboratory methods
Routine daptomycin susceptibility testing of Enterococcus isolates at MSKCC began in 2007 and was performed according to recommendations of the Clinical and Laboratory Standards Institute (CLSI).4 Susceptibility testing is performed using Microscan Gram-Positive Dried Panel 26 and read on autoSCAN-4 instruments (Siemens). Daptomycin dilutions in the panel ranged from 0.25 to 4 μg/mL and included the CLSI-recommended calcium supplementation. CLSI recommends that any isolates for which the minimum inhibitory concentration (MIC) is greater than 4 μg/mL be considered nonsusceptible. In this report, a daptomycin-resistant VRE is defined as an isolate with an MIC of greater than 4 μg/mL. Additional testing was conducted at Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, using the broth microdilution method (cation-adjusted Mueller-Hinton broth). Pulsed-field gel electrophoresis (PFGE) was performed after SmaI digestion and interpreted according to criteria previously described.5
Statistical analysis
Poisson regression was used to perform time-trend analysis on VRE healthcare-associated infection (HAI) rates from 2005 through 2009. The proportion of isolates resistant to daptomycin was analyzed using the Cochran-Armitage test for linear trend. A P value ≤.05 was considered statistically significant. All analyses were performed using SAS, version 9.1 (SAS Institute).
RESULTS
From 2005 through 2009, VRE HAI rates did not change significantly at MSKCC: 0.79 cases per 1,000 patient-days in 2005 and 0.84 cases per 1,000 patient-days in 2009 (P = .44). No VRE outbreaks were identified. Daptomycin use (measured in doses) increased almost 4-fold during the 5-year interval (Figure 1).
FIGURE 1.
Daptomycin use (shown with bars on left axis) and percentage of patients with daptomycin-resistant vancomycin-resistant enterococci (VRE) infections (represented by dotted and solid lines on right axis).
From 2007 through 2009, 176 patients had VRE bacteremia at MSKCC, including 18 (10.2%) with bacteremia due to daptomycin-resistant VRE. All resistant strains were Enterococcus faecium. Overall at MSKCC, 95% of all VRE isolates are E. faecium. The percentage of patients with bacteremia due to a daptomycin-resistant VRE strain increased significantly, from 3.4% (2 of 58) in 2007 to 15.2% (10 of 66) in 2009 (P = .03) (Figure 1).
Of 18 patients with daptomycin-resistant VRE bacteremia, 15 (83%) had underlying hematologic malignancy (Table 1), 16 (89%) had no prior exposure to daptomycin, and 2 patients had received daptomycin for 5 and 17 days before the diagnostic culture sample was obtained. Of the 18 patients, 11 (61%) had mixed bacteremia, with isolation of daptomycin-susceptible and daptomycin-resistant strains during the same episode. Of these, only 1 had received daptomycin before or during the VRE bacteremia episode.
TABLE 1.
Clinical Characteristics of 18 Patients with Bloodstream Infections due to Daptomycin-Resistant Vancomycin-Resistant Enterococci (VRE) at Memorial Sloan-Kettering Cancer Center (2007—2009)
| Duration of prior exposure, days |
||||||||
|---|---|---|---|---|---|---|---|---|
| Year, patient no. |
Age, sex | Underlying cancer | DAP | VANC | Treatment | 30-day mortality |
Duration of bacteremia, days |
Isolate resistance profile |
| 2009 | ||||||||
| 1 | 71, F | Breast | 0 | 90 | None | Yes | 1 | DAP resistant only |
| 2 | 6, F | NB | 5 | 16 | DAP | No | 10 | Mixed with DAP susceptible |
| 3 | 55, M | AML | 0 | 134 | LZD | Yes | 1 | DAP resistant only |
| 4 | 80, F | Ovarian | 0 | 2 | LZD | Yes | 4 | Mixed with DAP susceptible |
| 5 | 58, F | CLL | 0 | 20 | LZD | No | 2 | DAP resistant only |
| 6 | 66, F | Lymphoma | 0 | 0 | LZD | No | 1 | DAP resistant only |
| 7 | 79, M | Lung | 0 | 0 | LZD | Yes | 1 | DAP resistant only |
| 8 | 57, F | ALL-DUCBT | 0 | 13 | DAP gent | Yes | 18 | LZD and DAP resistant |
| 9 | 32, M | ALL-DUCBT | 0 | 31 | DAP, LZD | No | 9 | Mixed with DAP susceptible |
| 10 | 68, M | AML-PBSCT | 0 | 37 | LZD | No | 7 | Mixed with DAP susceptible |
| 2008 | ||||||||
| 11 | 25, M | AML | 0 | 2 | LZD | Yes | 15 | Mixed with DAP susceptible |
| 12 | 61, F | MDS/AML | 0 | 47 | LZD | No | 1 | Mixed with DAP susceptible |
| 13 | 60, F | Lymphoma | 0 | 26 | LZD | No | 1 | DAP resistant only |
| 14 | 65, F | MDS/PBSCT | 0 | 15 | LZD | No | 3 | Mixed with DAP susceptible |
| 15 | 68, M | Lymphoma/PBSCT | 0 | 1 | LZD | No | 2 | Mixed with DAP susceptible |
| 16 | 26, M | ALL/PBSCT | 0 | 49 | LZD | No | 4 | Mixed with DAP susceptible |
| 2007 | ||||||||
| 17 | 64, M | AML | 17 | 39 | LZD | Yes | 5 | DAP resistant only |
| 18 | 72, M | AML | 0 | 19 | LZD | No | 1 | Mixed with DAP susceptible |
note. ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; DAP, daptomycin; DUCBT, double umbilical cord blood transplant; gent, gentamicin; LZD, linezolid; MDS, myelodysplastic syndrome; NB, neuroblastoma; PBSCT, peripheral blood stem cell transplant; VANC, vancomycin.
Isolates from 14 of the 18 patients with daptomycin-resistant VRE bacteremia were available for additional testing by the CDC; all 14 isolates had a daptomycin MIC in the resistant range (8 μg/mL or greater), concordant with susceptibility testing performed at MSKCC.
Seven PFGE patterns were found among the 14 isolates. One common clone was isolated from 7 patients; however, these patients were not linked to each other in time or space. Serial VRE isolates from the same patient that showed different susceptibility to daptomycin demonstrated a clonal pattern by PFGE.
DISCUSSION
Daptomycin is a lipopeptide antibiotic that was first licensed for use in the United States in 2003. Daptomycin has bactericidal activity against methicillin-resistant Staphylococcus aureus and VRE and is currently approved for complicated skin and soft-tissue infections caused by certain gram-positive organisms, including Enterococcus faecalis (vancomycin-susceptible isolates only).
Data on the efficacy of daptomycin in treatment of infections due to VRE are limited. Despite this, daptomycin is often used to treat serious VRE infections because of limited antibiotic options, less frequent administration, fewer side effects, less potential for drug-drug interactions, and in vitro bactericidal activity against VRE.
Premarketing and surveillance studies6 have suggested that daptomycin resistance among VRE isolates is rare. The mechanism of resistance has not been completely elucidated, and mobile genetic elements that confer resistance have not been identified.7 A few reports of de novo resistance to daptomycin8,9 and that occurring during treatment10,11 have emerged in recent years. However, postmarketing surveillance of VRE isolates collected from US medical centers from 2007 through 2008 showed that 99.5% of E. faecium and 100% of E. faecalis isolates remain susceptible to daptomycin.3
Our study has several important findings. First, we have reported a statistically significant increase in daptomycin-resistant VRE isolates despite variable use of the drug during the study years. In 2009, 15% of patients with VRE bacteremia and VRE isolated from other clinical samples (Figure 1) demonstrated resistance to daptomycin, much higher than recent surveillance reports from US centers.3
Second, the majority of patients (89%) with bacteremia due to daptomycin-resistant VRE strains had no prior exposure to daptomycin and did not receive daptomycin for treatment of VRE bacteremia. Nosocomial transmission is certainly a possibility, although we did not find any epidemiologic link between these patients. Seven of 14 blood isolates that were typed by PFGE showed a common clone, which is endemic among VRE isolates at MSKCC.
Third, 61% of patients with daptomycin-resistant VRE bacteremia (Table 1) had mixed infection that included both resistant and susceptible strains, a finding that has important implications for management of these infections and emergence of resistance during treatment.
Our study has several limitations. We confirmed the results of our susceptibility testing with the CLSI broth microdilution method on blood isolates only. However, the proportion of daptomycin resistant VRE in blood and isolates from all sites was roughly the same, suggesting this is unlikely to change our findings. Second, we might have had an undiscerned outbreak of daptomycin resistant VRE. However patients sharing a common strain were not linked in time or space; furthermore the common strain of VRE isolated from seven patients is common in our hospital and was present long before acquiring the resistant phenotype.
In conclusion, resistance to daptomycin among VRE isolates is steadily emerging among patients with cancer at our hospital and may occur without prior daptomycin exposure. Susceptibility to daptomycin should be routinely evaluated for all VRE isolates, and empiric daptomycin therapy for VRE infections without the availability of susceptibility data should be used with caution.
ACKNOWLEDGMENTS
We thank Dr. Jean Patel (CDC) for susceptibility testing, Crystal Son for statistical analysis, and Dr. Robin Patel (Mayo) and Ms. Perminder Khosa for pulsed-field gel electrophoresis typing and analysis.
Financial support. This work was supported by a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (Career Development Award, grant MK-K23AI083880) to M.K.
Footnotes
Potential conflicts of interest. All authors report no conflicts of interest relevant to this article.
REFERENCES
- 1.National Nosocomial Infections Surveillance (NNIS) System NNIS report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 32(8):470–485. doi: 10.1016/S0196655304005425. [DOI] [PubMed] [Google Scholar]
- 2.DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. 2005;41(3):327–333. doi: 10.1086/430909. [DOI] [PubMed] [Google Scholar]
- 3.Sader HS, Jones RN. Antimicrobial susceptibility of gram-positive bacteria isolated from US medical centers: results of the Daptomycin Surveillance Program (2007–2008) Diagn Microbiol Infect Dis. 2009;65(2):158–162. doi: 10.1016/j.diagmicrobio.2009.06.016. [DOI] [PubMed] [Google Scholar]
- 4.Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing—Twentieth Information Supplement. CLSI; Wayne, PA: 2010. CLSI document M100-S20. [Google Scholar]
- 5.Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol. 1995;33(9):2233–2239. doi: 10.1128/jcm.33.9.2233-2239.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Silverman JA, Oliver N, Andrew T, Li T. Resistance studies with daptomycin. Antimicrob Agents Chemother. 2001;45(6):1799–1802. doi: 10.1128/AAC.45.6.1799-1802.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Montero CI, Stock F, Murray PR. Mechanisms of resistance to daptomycin in Enterococcus faecium. Antimicrob Agents Chemother. 2008;52(3):1167–1170. doi: 10.1128/AAC.00774-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lesho EP, Wortmann GW, Craft D, Moran KA. De novo daptomycin nonsusceptibility in a clinical isolate. J Clin Microbiol. 2006;44(2):673. doi: 10.1128/JCM.44.2.673.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fraher MH, Corcoran GD, Creagh S, Feeney E. Daptomycin-resistant Enterococcus faecium in a patient with no prior exposure to daptomycin. J Hosp Infect. 2007;65(4):376–378. doi: 10.1016/j.jhin.2007.01.002. [DOI] [PubMed] [Google Scholar]
- 10.Lewis JS, II, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother. 2005;49(4):1664–1665. doi: 10.1128/AAC.49.4.1664-1665.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Long JK, Choueiri TK, Hall GS, Avery RK, Sekeres MA. Daptomycin-resistant Enterococcus faecium in a patient with acute myeloid leukemia. Mayo Clin Proc. 2005;80(9):1215–1216. doi: 10.4065/80.9.1215. [DOI] [PubMed] [Google Scholar]