Antimicrobial activity of daptomycin and selected
comparators tested against bloodstream
Staphylococcus aureus
isolates from hemodialysis
patients
Helio S. Sader
a,b,*
, Thomas R. Fritsche
a, Ronald N. Jones
a,caJMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, Iowa 52317, USA bUniversidade Federal de Sao Paulo, Sao Paulo, Brazil
cTufts University School of Medicine, Boston, Massachusetts, USA
Received 25 March 2008; received in revised form 30 May 2008; accepted 14 July 2008
Corresponding Editor:J. Peter Donnelly, Nijmegen, The Netherlands
Introduction
Patients on long-term hemodialysis are at a significantly higher risk for catheter-related bloodstream infections
http://intl.elsevierhealth.com/journals/ijid
KEYWORDS
Hemodialysis; Daptomycin;
Staphylococcus aureus; Catheter infection; Bacteremia;
Bloodstream infection
Summary
Background: Patients on long-term hemodialysis are at a significantly higher risk for catheter-related bloodstream infections (BSI) than the general population. These infections are generally caused by Gram-positive organisms, especiallyStaphylococcus aureus. In the present study, we evaluated the antimicrobial susceptibility patterns ofS. aureuscausing BSI in dialysis patients compared to those causing BSI in other patient populations.
Methods: The potencies of daptomycin and various comparator agents were evaluated by reference broth microdilution methods forS. aureusbloodstream isolates from dialysis patients (606 strains) in 43 hospitals in North America and Europe. Susceptibility patterns for the dialysis isolate set were compared to thoseS. aureuscausing BSI in other patient populations in the same hospitals and time period.
Results: Daptomycin was highly potent againstS. aureuscausing bacteremia in dialysis patients (MIC50/MIC90, 0.25/0.5mg/ml). Vancomycin (MIC50/MIC90, 1/1mg/ml) and linezolid (MIC50/
MIC90, 2/2mg/ml) showed similar potency, and overall susceptibility rates for the three
anti-biotics were 99.8—100.0% susceptible. Linezolid and vancomycin were four- to eight-fold less potent than daptomycin.
Conclusions: The overall susceptibility patterns ofS. aureusstrains from dialysis patients were very similar to those of non-dialysis patients.
#2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address:[email protected](H.S. Sader).
(BSI). Infection, mainly septicemia, is second to cardiovas-cular disease as the leading cause of death in patients with end-stage renal disease (ESRD) in the USA.1—3In fact, cathe-ters account for a significant proportion of septicemia in this population. In a prospective study performed a decade ago, 40% of hemodialysis patients dialyzed by central venous catheters developed potentially life-threatening bacteremic complications, including infective endocarditis, septicemia, and osteomyelitis.4 In a more recent study,5 the overall incidence of septicemia was 10.4 first events per 100 patient-years. Compared with hemodialysis patients with fistulas for dialysis access, peritoneal dialysis patients and hemodialysis patients dialyzed with synthetic grafts had similar risks of septicemia. Even with adjustment for differ-ences in comorbidity, the risk of septicemia was almost twice as high in patients using central venous catheters, whether tunneled or non-tunneled.5Similar rates have been reported in a multicenter, prospective study of patients beginning maintenance dialysis therapy in the USA between 1995 and 1998.6
These infections are generally caused by Gram-positive organisms, especiallyStaphylococcus aureus, which has been associated with the most devastating metastatic complica-tions due to the tropism for heart valves and bone. Further-more, vascular access-related BSI and related complications requiring hospitalization account for nearly one-third of the cost of ESRD management, with reported mortality rates of 12—26%.7,8
Daptomycin is a lipopeptide antimicrobial agent with potent in vitro activity against Gram-positive cocci.9—11 Daptomycin does not exhibit cross-resistance with other known classes of antimicrobials and also has a low risk for development of spontaneous mutational resistance. Indeed, daptomycin has been shown to be active against methicillin-resistantS. aureus(MRSA),S. aureusresistant to linezolid or quinupristin/dalfopristin, vancomycin-resistant enterococci (VRE), and macrolide-resistant streptococci.11—13 Daptomy-cin was approved by the United States Food and Drug Admin-istration (USA-FDA) and by the European Medicines Agency (EMEA) for the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillinsusceptible and -resistantS. aureus, groups A and Bb-hemolytic streptococci, and for vancomycin-susceptibleEnterococcus faecalis. This compound has also been approved for the treatment ofS. aureusbacteremia and right-sided infective endocarditis.14 In the present study, we evaluated the antimicrobial suscept-ibility patterns ofS. aureuscausing BSI in dialysis patients compared to those causing BSI in other patient populations.
Materials and methods
As part of the Daptomycin Surveillance Program, 606 S. aureusstrains causing BSI in dialysis patients were collected from 43 hospitals in North America and Europe in 2002—2006. Susceptibility patterns of strains from dialysis patients were compared to those of 1212S. aureusstrains (randomized at 2:1) causing BSI in non-dialysis patients. For each strain from a dialysis patient, two strains from BSI in non-dialysis patients hospitalized in the same hospital and time period were included as the control group. A third group of strains used for comparison included allS. aureusstrains collected by the JMI Laboratories (North Liberty, IA, USA) from BSI in North American and European medical centers in the 2002—2006 period, excluding the group of strains from dialysis patients (12 191 strains).
Daptomycin and more than 20 comparator agents were tested using the Clinical Laboratory Standards Institute (CLSI) M7-A7 broth microdilution method.15,16 All strains were tested in validated, broth microdilution panels manufactured by TREK Diagnostics (Cleveland, OH, USA). Mueller—Hinton broth adjusted to contain physiological levels of calcium (50 mg/l) was used when testing daptomycin. The USA-FDA and CLSI approved daptomycin susceptibility breakpoint for
S. aureus (1mg/ml) was applied. The following quality control (QC) organisms were concurrently tested:E. faecalis
ATCC 29212,S. aureusATCC 29213, andStreptococcus pneu-moniae ATCC 49619; all results were within published QC ranges.16
Results
Daptomycin was highly active againstS. aureusisolates from dialysis patients (MIC50, 0.25mg/ml; MIC90, 0.5mg/ml) with
only one strain (0.16%) showing decreased susceptibility to this compound (MIC of 2mg/ml;Table 1). Daptomycin MIC distribution ofS. aureusBSI strains from dialysis patients was very similar to those of the other two groups ofS. aureus
strains evaluated (control group and all BSI strains) with 72.6—76.2% of strains inhibited at0.25mg/ml and 98.8— 99.5% inhibited at0.5mg/ml of daptomycin (Table 1).
Susceptibility rates for most of the antimicrobial agents were similar among theS. aureusgroups evaluated (Table 2). Oxacillin susceptibility rates were relatively low among all groups (60.4—61.8% susceptible). Erythromycin (44.6—47.0% susceptibility), levofloxacin (59.9—62.0%), and clindamycin (75.2—79.0%) also exhibited limited activity among all groups
Table 1 Daptomycin MIC distributions forStaphylococcus aureusisolated from BSI in dialysis patients when compared to those causing BSI in two non-dialysis patient populations
Organism group (No. of isolates) Number of isolates (cumulative %) inhibited at daptomycin MIC (mg/ml) of:
0.12 0.25 0.5 1 2 4
Dialysis patients (606) 28 (4.6) 412 (72.6) 159 (98.8) 6 (99.8) 1 (100.0)
-Control groupa(1212) 55 (4.5) 869 (76.2) 282 (99.5) 6 (100.0) -
-Bloodstream infectionb(12 191) 552 (4.5) 8569 (74.8) 2979 (99.3) 85 (>99.9) 5 (>99.9) 1 (100.0)
BSI, blood stream infection; MIC, minimum inhibitory concentration.
ofS. aureus. Mupirocin activity was slightly lower amongS. aureus strains from dialysis patients (94.2% susceptible at
8mg/ml) compared to the other two groups (95.7—96.0%). Daptomycin (MIC50 of 0.25mg/ml and MIC90of 0.5mg/ml),
vancomycin (MIC50and MIC90of 1mg/ml), and linezolid (MIC50
and MIC90 of 2mg/ml) were the most active compounds
tested. Although these compounds showed similar suscept-ibility rates (99.8—100.0%), daptomycin was four- to eight-fold more active than vancomycin or linezolid (Table 2). Resistance to oxacillin did not adversely affect the activity of these compounds (data not shown).S. aureusisolates from the control group (randomized at 2:1 ratio; 1212 strains) exhibited susceptibility patterns very similar to those of strains from dialysis patients (Table 2). A third group of strains (BSI group), which included allS. aureusBSI strains collected by the monitor during the same time period, also showed susceptibility patterns comparable to those of strains from dialysis patients and the control group (Table 2).
Daptomycin MIC values higher than the susceptible break-point of 1mg/ml were observed in only six strains of the large group (0.05% of 12 191 strains). Five strains had a daptomycin MIC value of 2mg/ml. Only one strain had a MIC value of 4mg/ ml for daptomycin (<0.01%). Isolates with a daptomycin MIC of
2mg/ml showed vancomycin MIC values of 2mg/ml, and the strain with daptomycin MIC of 4mg/ml exhibited vancomycin MIC of 4mg/ml (vancomycin-intermediate or VISA phenotype). Four strains with decreased susceptibility to vancomycin were observed in the all BSI group, each having a vancomycin MIC of 4mg/ml. Three of those strains were susceptible to daptomycin (MIC 0.5—1mg/ml), while the fourth strain was the daptomycin isolate with a MIC value of 4mg/ml. More-over, five strains showed elevated linezolid MIC values, three strains with a MIC value of 4mg/ml (susceptible) and twoS. aureusisolates that were non-susceptible to linezolid, one each with a MIC value of 8mg/ml and 16mg/ml. All isolates with elevated linezolid MIC values (4mg/ml) were suscep-tible to daptomycin (MIC 0.25—0.5mg/ml) and vancomycin (MIC 1mg/ml). The linezolid non-susceptible strains (MIC
8mg/ml) were isolated in the USA in Seattle, Washington,
and Des Moines, Iowa, and both had a G2576T mutation in domain V of the 23S rRNA.
Discussion
S. aureusis a leading cause of BSI and other invasive infec-tions, and dialysis patients are especially vulnerable toS. aureusinfections, frequently those caused by antimicrobial-resistant strains (MRSA). It is estimated that, in 2005, the incidence of invasive MRSA infection among dialysis patients was 45.2 cases per 1000 population in the USA.17 Persons receiving dialysis can be at higher risk for infection with invasive MRSA compared with the general population, in which rates of invasive MRSA have ranged from 0.2 to 0.4 infections per 1000 population.18 Furthermore, infections represent the second most common cause of death in patients with ESRD, accounting for nearly 14% of deaths.18
Antimicrobial treatment for dialysis-associated infections is one of the factors increasing the prevalence of antimicro-bial resistance. MRSA strains of healthcare origin are typically multidrug-resistant. In the USA, five of six first patients reported with VISA had received dialysis, and the first case of vancomycin-resistant S. aureus (VRSA) was a dialysis patient.17,19 Vancomycin clearances vary substantially according to the type of dialysis. The compound is not significantly dialyzable when hemodialysis is performed using a low flux membrane such as cuprophan, but it is considerably dialyzable when hemodialysis is performed using a high flux membrane such as polysulfone, polyacrylonitrile, and poly-methylmethacrylate. Continuous renal replacement therapy also increases total body clearance of vancomycin. However, quantification of vancomycin removal is difficult to estimate with any type of hemodialysis, and monitoring plasma levels of the drug is highly recommended.20 Inappropriate dosage adjustment may lead to either toxic side effects levels or long periods of low trough levels, which may facilitate the emer-gence of vancomycin-resistant strains.19—22
Daptomycin plasma protein binding is approximately 92% and its elimination is primarily achieved by renal
Table 2 Antimicrobial susceptibility patterns ofS. aureusisolated from BSI in dialysis patients compared to those causing BSI in non-dialysis patients (two groups)
Antimicrobial agents Dialysis (606) Control (1212) BSI (12 191)
MIC90 % susceptible MIC90 % susceptible MIC90 % susceptible
Daptomycin 0.5 99.8a 0.5 100.0 0.5 >99.9
Oxacillin >2 60.4 >2 60.6 >2 61.8
Erythromycin >8 47.0 >8 45.7 >8 44.6
Clindamycin >8 78.5 >8 79.0 >8 75.2
Levofloxacin >4 60.9 >4 59.9 >4 62.0
Mupirocin 4 94.2b 4 95.7b 4 96.0b
Trimethoprim/sulfamethoxazole 0.5 98.2 0.5 97.3 0.5 97.0
Quinupristin/dalfopristin 0.5 99.7 0.5 99.5 0.5 99.8
Linezolid 2 99.8c 2 100.0 2 >99.9
Vancomycin 1 100.0 1 100.0 1 >99.9d
BSI, blood stream infection; MIC, minimum inhibitory concentration. aOne non-susceptible strain with daptomycin MIC at 2mg/ml. bMIC8mg/ml.
excretion of unchanged drug.23The mean urinary recovery over a 24-hour period is 50% to 60% of the administered dose in healthy adults. The recommended dose of dapto-mycin is 4 mg/kg/day for treatment of cSSSI and 6 mg/kg/ day for treatment of bacteremia and endocarditis. It is administered intravenously once daily for patients with creatinine clearances 30 ml/min. Hence, in patients with reduced renal function (creatinine clearances
<30 ml/min), including those receiving hemodialysis or
continuous ambulatory peritoneal dialysis, the recom-mended dose interval is 48 hours.23 In addition, more recent studies indicate that extended daily dialysis, an extracorporeal renal replacement therapy that is increas-ingly used in intensive care units, eliminates daptomycin effectively and to a larger extent than intermittent hemo-dialysis. Thus, patients on extended daily dialysis may require higher daptomycin doses than those on intermit-tent hemodialysis.24
In the present study, vancomycin, linezolid, and dapto-mycin were the most active compounds tested against S. aureuscausing BSI in dialysis patients, as well as against a large collection ofS. aureusBSI strains collected in North America and Europe. Vancomycin has been the standard antimicrobial therapy for serious MRSA infections since the early 1980 s, when MRSA emerged as a significant noso-comial pathogen.25However, vancomycin has demonstrated slower in vitro bactericidal activity and suboptimal clinical response compared with antistaphylococcal beta-lac-tams.25,26
Vancomycin-susceptible MRSA strains show a considerable heterogeneity in vitro with respect to vancomycin MIC and killing, and these differences appear to affect the clinical efficacy and the probability of successful treatment of MRSA BSI. Although the clinical importance of bactericidal activity in the treatment of most infections remains controversial, antimicrobial treatments that provide bactericidal therapy have been shown to be superior to bacteriostatic regimens in the treatment ofS. aureusBSI, especially in endocarditis.25— 27Sakoulas et al. evaluated 30 MRSA strains from 30 patients with bacteremia and showed a statistically significant rela-tionship between treatment success with vancomycin and decrease in vancomycin MIC values (0.5mg/ml compared to 1—2mg/ml;p= 0.02) and the degree of killing (reduction in log10CFU/ml).26
In contrast to vancomycin and linezolid, daptomycin has rapid, concentration-dependent bactericidal activity against S. aureusand has demonstrated excellent results in the treatment ofS. aureusBSI.11,27This in vitro bacter-icidal activity is maintained at high inoculum concentrations and against bacteria in the stationary growth phase. Furthermore, daptomycin has demonstrated a prolonged, concentration-dependent post-antibiotic effect,10and good results in treating staphylococcal (Staphylococcus epider-midisandS. aureus) biofilms in a central venous catheter model.28
In summary, daptomycin exhibited sustained activity against a large collection of S. aureus collected from BSI (2002—2006 sample), including strains from dialysis patients. Because of its excellent anti-S. aureus spectrum, high potency, and rapid bactericidal activity, daptomycin repre-sents an excellent treatment option for BSI caused by S. aureusin at-risk patients such as those on hemodialysis.
Acknowledgements
We express our appreciation to the following individuals for assistance with technical support, manuscript preparation, and editorial processing: N. O’Mara-Morrissey, P. Rhomberg, and M. Stillwell. This study was funded by a research grant from Cubist Pharmaceuticals, Inc., and was presented in part at the 45th Infectious Diseases Society of America (IDSA) meeting, San Diego, CA, USA, October 4—7, 2007.
Conflict of interest:JMI Laboratories, Inc. has received research/education grants in the last two years from: AB BIODISK, Abbott, API, Arpida, Astellas, AstraZeneca, Avexa, Bayer, bioMerieux, Cadence, Cempra, Cerexa, Chiron, Cor-nerstone, Cubist, Daiichi, Elan, Elanco, Enanta, GlaxoS-mithKline, Johnson & Johnson (Ortho McNeil), Merck, Novartis, Optimer, Ordway, Osmotics, Pacific Beach, Penin-sula, Pfizer, Protez, Replidyne, Schering-Plough, Sequoia, Shionogi, Theravance, TREK Diagnostics, ViroPharma, and Wyeth.
References
1. Foley RN. Infections in patients with chronic kidney disease. Infect Dis Clin North Am2007;21:659—72. viii.
2. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int2000;58:1758—64.
3. Thomson PC, Stirling CM, Geddes CC, Morris ST, Mactier RA. Vascular access in haemodialysis patients: a modifiable risk factor for bacteraemia and death.QJM2007;100:415—22. 4. Marr KA, Sexton DJ, Conlon PJ, Corey GR, Schwab SJ, Kirkland
KB. Catheter-related bacteremia and outcome of attempted catheter salvage in patients undergoing hemodialysis.Ann Intern Med1997;127:275—80.
5. Ishani A, Collins AJ, Herzog CA, Foley RN. Septicemia, access and cardiovascular disease in dialysis patients: the USRDS Wave 2 study.Kidney Int2005;68:311—8.
6. Gupta R, Plantinga LC, Fink NE, Melamed ML, Coresh J, Fox CS, et al.Statin use and sepsis events [corrected] in patients with chronic kidney disease.JAMA2007;297:1455—64.
7. Liu JW, Su YK, Liu CF, Chen JB. Nosocomial blood-stream infec-tion in patients with end-stage renal disease: excess length of hospital stay, extra cost and attributable mortality.J Hosp Infect 2002;50:224—7.
8. Saxena AK, Panhotra BR. Haemodialysis catheter-related blood-stream infections: current treatment options and strategies for prevention.Swiss Med Wkly2005;135:127—38.
9. Hair PI, Keam SJ. Daptomycin: a review of its use in the manage-ment of complicated skin and soft-tissue infections and Staphy-lococcus aureusbacteraemia.Drugs2007;67:1483—512. 10. Wiedemann B. Test results: characterising the antimicrobial
activity of daptomycin.Clin Microbiol Infect2006;12:9—14. 11. Sauermann R, Rothenburger M, Graninger W, Joukhadar C.
Dap-tomycin: a review 4 years after first approval.Pharmacology 2008;81:79—91.
12. Pfaller MA, Sader HS, Jones RN. Evaluation of the in vitro activity of daptomycin against 19 615 clinical isolates of Gram-positive cocci collected in North American hospitals (2002—2005).Diagn Microbiol Infect Dis2007;57:459—65.
15. Clinical, Laboratory Standards Institute.Methods for dilution antimicrobial susceptibility tests for bacteria that grow aero-bically; approved standard. M7-A7. 7th ed. Wayne, PA: CLSI; 2006.
16. Clinical, Laboratory Standards Institute.Performance standards for antimicrobial susceptibility testing. M100-S17. 17th Infor-mational Supplement. Wayne, PA: CLSI; 2007.
17. Invasive methicillin-resistantStaphylococcus aureusinfections among dialysis patients–—United States, 2005. Centers for Dis-ease Control and Prevention.MMWR Morb Mortal Wkly Rep 2007;56:197—9.
18. Fridkin SK, Hageman JC, Morrison M, Sanza LT, Como-Sabetti K, Jernigan JA,et al.Methicillin-resistantStaphylococcus aureus disease in three communities. N Engl J Med 2005;352: 1436—44.
19. Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robin-son-Dunn B, et al. Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylo-coccus aureusWorking Group.N Engl J Med1999;340:493—501. 20. Kielstein JT, Czock D, Schopke T, Hafer C, Bode-Boger SM, Kuse E, et al.Pharmacokinetics and total elimination of meropenem and vancomycin in intensive care unit patients undergoing extended daily dialysis.Crit Care Med2006;34:51—6.
21. Launay-Vacher V, Izzedine H, Mercadal L, Deray G. Clinical review: use of vancomycin in haemodialysis patients.Crit Care 2002;6:313—6.
22. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomy-cin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity.Antimicrob Agents Che-mother2008;52:1330—6.
23. Dvorchik B, Arbeit RD, Chung J, Liu S, Knebel W, Kastrissios H. Population pharmacokinetics of daptomycin.Antimicrob Agents Chemother2004;48:2799—807.
24. Burkhardt O, Joukhadar C, Traunmuller F, Hadem J, Welte T, Kielstein JT. Elimination of daptomycin in a patient with acute renal failure undergoing extended daily dialysis.J Antimicrob Chemother2008;61:224—5.
25. Gould IM. MRSA bacteraemia. Int J Antimicrob Agents 2007;30(Suppl 1):S66—70.
26. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering Jr RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicil-lin-resistantStaphylococcus aureusbacteremia.J Clin Microbiol 2004;42:2398—402.
27. Fowler Jr VG, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME,et al.Daptomycin versus standard therapy for bacter-emia and endocarditis caused byStaphylococcus aureus.N Engl J Med2006;355:653—65.
