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Clinical outcomes associated with linezolid resistance in leukemia patients with linezolid-resistant Staphylococcus epidermidis bacteremia

Clinical outcomes associated with linezolid resistance in leukemia patients with... Clinical outcomes associated with linezolid resistance in leukemia patients with linezolid-resistant Staphylococcus epidermidis bacteremia a a a b b Stephanie A. Folan ; Kayleigh R. Marx ; Frank P. Tverdek ; Issam Raad ; Victor E. Mulanovich , c b,d,e a,e* Jeffrey J. Tarrand ; Samuel A. Shelburne ; Samuel L. Aitken a – Division of Pharmacy; b – Department of Infectious Diseases, Infection Control, and Employee Health; c – Department of Laboratory Medicine; d – Department of Genomic Medicine; The University of Texas MD Anderson Cancer Center, Houston, TX; e – Center for Antimicrobial Resistance and Microbial Genomics UTHealth McGovern Medical School, Houston, TX *Person to whom correspondence should be addressed: Samuel L. Aitken, PharmD, BCPS (AQ-ID) Division of Pharmacy (Unit 0090) MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Phone: +1 (713) 745-3968 Fax: +1 (713) 792-5256 Email: SLAitken@mdanderson.org Keywords: Febrile neutropenia; catheter-related bloodstream infection; staphylococci; antimicrobial stewardship; hematologic malignancy © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Summary: Linezolid resistance is increasingly reported worldwide, but the clinical significance of linezolid resistance is unclear. We show that linezolid resistance is associated with prolonged bacteremia in leukemia patients with Staphylococcus epidermidis bacteremia treated empirically with linezolid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Background: Coagulase-negative staphylococci, including S. epidermidis, are the most common cause of bloodstream infection in cancer patients. Linezolid resistance is increasingly identified in S. epidermidis but whether such resistance alters the clinical course of S. epidermidis infections is unknown. The purpose of this study was to assess the clinical impact of linezolid resistance in leukemia patients with S. epidermidis bloodstream infection. Methods: This was a retrospective, single-center, cohort study of all adult leukemia patients with S. epidermidis bacteremia treated with empiric linezolid between 2012 and 2015. The primary endpoint was adverse clinical outcome on day three, defined as a composite of persistent bacteremia, fever, ICU admission, or death. Fourteen and 30-day mortality were also assessed. Results: Eighty-two unique leukemia patients with S. epidermidis were identified. Linezolid resistance was identified in 33/82 (40%). Patients with linezolid-resistant S. epidermidis were more significantly more likely to have persistent bacteremia (41% vs 7%; adjusted relative risk [aRR] 5.15, 95% CI 1.63 – 16.30; p =0.005), however, adverse short-term clinical outcomes overall were not more common among patients with linezolid-resistant S. epidermidis (61% vs 33%; aRR 1.46, 95% CI 0.92 – 2.32; p = 0.108). No differences were observed in 14- and 30-day mortality. Conclusion: Leukemia patients with linezolid-resistant S. epidermidis bacteremia who were treated with linezolid were significantly more likely to have persistent bacteremia compared to those with linezolid-sensitive isolates. Interventions to limit the clinical impact of linezolid resistant S. epidermidis are warranted. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Background Coagulase-negative Staphylococcus (CoNS), including Staphylococcus epidermidis, are the leading cause of catheter-related bloodstream infections (BSI) in the general hospital population and are responsible for 30% of BSI in patients with hematologic malignancy [1]. The use of linezolid for infections suspected or known to be caused by Gram-positive bacteria is increasing due to the rise in drug-resistant microorganisms and concerns for nephrotoxicity caused by vancomycin [2, 3]. Globally, approximately 2% of CoNS are resistant to linezolid, however resistance rates may be higher in institutions with high rates of linezolid usage [4, 5]. Clonal dissemination of linezolid-resistant S. epidermidis (LRSE) is increasingly reported in diverse settings worldwide although prior studies have not assessed the clinical impact of LRSE [6-11]. At our institution, LRSE occurs nearly exclusively in patients with leukemia and is associated with epidemic spread of a clonal complex 5 (CC5) strain with a cfr-harboring plasmid [5, 12]. A case-control study performed in Italy identified higher 30-day mortality in patients with linezolid-resistant compared to linezolid-susceptible staphylococci, however, no information was provided on the antimicrobials used for the treatment of these infections [13]. To our knowledge, no prior studies have examined mortality in relation to linezolid being used as treatment for LRSE BSI. Thus, we sought to test the hypotheses that LRSE bacteremia empirically treated with linezolid would have worse clinical outcomes in comparison to patients infected by linezolid-sensitive strains. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Methods Study design We performed a retrospective cohort study of adult patients (aged ≥ 18 years) with leukemia (including acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], and others) or the myelodysplastic syndrome (MDS) and laboratory-confirmed S. epidermidis bacteremia who received empiric linezolid treatment at the University of Texas MD Anderson Cancer Center from July 1, 2012 to July 22, 2015. Patients with prior hematopoietic stem cell transplant (HSCT) were included if in relapse at the time of S. epidermidis bacteremia. At our institution, CoNS are not routinely identified to the species level unless laboratory-defined criteria suggestive of true infection (i.e., culture positivity from more than one blood draw site or >10 colony forming units [CFU] from a single site) are met. To further limit the reporting of contaminated blood cultures, cultures positive for <10 CFU of CoNS from a single site are not reported to the treating providers. CoNS that were not identified to the species level or CoNS species other than S. epidermidis were not included. Linezolid susceptibility was determined via Vitek 2 (bioMérieux, Marcy-L’Étoile, France) with a minimum inhibitory concentration (MIC) >4µg/mL considered resistant per current CLSI standards (https://clsi.org/standards/products/microbiology/documents/m100/); resistant isolates were confirmed by Etest (bioMérieux) per standard protocol in the clinical microbiology laboratory. Twelve isolates were missing data for the confirmatory Etest; these isolates were considered to be resistant based on prior experience demonstrating 100% concordance between Vitek 2 susceptibility resting and laboratory-confirmed resistance [12]. Patients were identified through microbiology laboratory records, and clinical information was collected from the electronic health record. Patients with more than one occurrence of S. epidermidis bacteremia were included only once. Endpoints and study definitions The primary endpoint was a composite of adverse short-term outcomes on day 3 after the index culture, defined as persistent bacteremia (isolation of S. epidermidis from blood > 3 days after the Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript index culture without an intervening negative blood culture), persistent fever (temperature ≥ 38°C on day 3), ICU admission, or death, each by day 3 following the index culture. Day 3 was chosen as this would approximate the time at which organism identification and susceptibility would be available and would therefore more closely reflect the impact of empiric therapy. As mortality due to this organism was expected to be low, 14-day and 30-day mortality were considered as secondary outcomes. Other secondary outcomes consisted of individual components of the composite endpoint and time to blood culture clearance (i.e., first recorded negative blood culture) within 7 days. Assessment of persistent bacteremia and time to blood culture clearance was limited to patients in which at least one followup blood culture was obtained. Empiric treatment with linezolid was defined as at least one dose of linezolid within one day of the date the positive index blood culture was obtained. Salvage chemotherapy was considered to be any chemotherapy administered after failed primary induction, relapsed disease, and/or enrollment in a clinical trial for either of these reasons. Severity of illness was assessed at the time of the index blood culture using the Pitt bacteremia score, a validated scoring system based on mental status, vital signs, requirement for mechanical ventilation, and recent cardiac arrest [14]. This protocol was approved by the Institutional Review Board at MD Anderson Cancer Center with a waiver of informed consent. Data was collected via electronic chart review and stored using REDCap (Vanderbilt University, Nashville, TN) [15]. Statistical analysis Baseline characteristics were compared using the Wilcoxon rank-sum and Fisher’s exact test, with all comparisons made between patients with linezolid-resistant and linezolid-susceptible isolates. After univariate analysis, multivariate Poisson regression with robust variance estimates, adjusting for clinically relevant confounders, was performed for the primary composite endpoint and persistent bacteremia. Poisson regression was chosen over logistic regression as the dependent Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript variables of interest had incidences greater than 10%, invalidating the assumption that the odds ratio approximates the relative risk [16]. No multivariate analyses were performed for other components of the composite endpoint as these were infrequent and not amenable to multivariate analysis. Fourteen and 30-day mortality and time to clearance of bacteremia were assessed using multivariate Cox proportional hazards modelling and Kaplan-Meier curves. As blood cultures were not obtained on a daily basis for most patients, the first date of a documented negative culture was considered to be the first negative day for the survival analysis. Patients with no follow-up cultures performed were removed from the time-to-event analysis for clearance of bacteremia. The proportional hazards assumptions were verified by visual assessment of the scaled Schoenfeld residuals. All multivariate models were constructed using a backwards stepwise approach, incorporating all variables with a univariate p-value < 0.2 and removing those with the largest p- value sequentially until only variables with a p-value < 0.2 remained. Removal of the central venous catheter (CVC) was not included in multivariate models to avoid adjusting for a downstream consequence of persistent bacteremia. Statistical analyses were performed via STATA v14.1 (StataCorp LP, College Station, TX). Results Cohort characteristics Eighty-two unique patients (median age 52 years, range 39 – 67; 52% male) were included in the study. Overall, 33 (40%) of S. epidermidis isolates were LRSE, with an MIC and MIC of 2 mcg/mL 50 90 and > 256 µg/mL, respectively. Among the 33 resistant isolates, 30/33 (91%) displayed high-level resistance with MICs of > 256 µg/mL. There were no statistically significant differences in clinical characteristics between patients with linezolid-resistant and linezolid-susceptible isolates (Table 1), except for neutropenia (absolute neutrophil count <500 cells/mm ) at the time of first positive blood culture (97% vs 67%, respectively; p=0.001) and nosocomial onset (55% vs 29%, Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript respectively; p=0.022). The majority of patients had acute myeloid leukemia (62%), followed by acute lymphoblastic leukemia (24%). In general patients had been extensively treated for their leukemia, with 73% receiving salvage chemotherapy and 29% having previously received an allogeneic hematopoietic stem cell transplant. However, the study population was not acutely ill, as reflected in the low median Pitt bacteremia score (0, interquartile range [IQR] 0-1). Most patients had a CVC (93%) and removal of the CVC within three days of bacteremia onset was similarly infrequent among patients with and without linezolid-resistant isolates (17% in each group, p = 0.987).. Outcomes assessment Composite outcome Seventy-four patients (90%) had at least one follow-up blood culture. Persistent bacteremia was significantly more common among patients with LRSE (41% vs 7%, p = 0.001) and remained significantly more common after adjustment for confounders (adjusted relative risk [aRR] 3.97, 95% confidence interval [CI] 1.23 – 12.86, p = 0.021).. No significant differences were observed for other components of the composite endpoint, including persistent fever (27% vs 24%, p = 0.801), ICU admission (15% vs 10%, p = 0.51), and death by day 3 (3% vs 2%, p = 1.000). Overall, the composite endpoint was significantly more frequent in patients with LRSE as compared to those with linezolid-susceptible bacteremia in univariate analysis (61% vs 33%, p = 0.023), however, no significant difference was observed after adjustment for other confounders (aRR 1.46; 95% confidence interval CI 0.92 – 2.32, p=0.108). Full Poisson regression models for the composite endpoint and persistent bacteremia are shown in Table 2 and Table 3. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 14- and 30-day mortality All deaths occurred among patients receiving salvage chemotherapy, therefore, mortality analysis was limited to this subgroup (n = 60). A trend towards increased unadjusted and adjusted mortality at day 14 was observed for patients with LRSE versus those without (21% vs 8%; adjusted hazard ratio [aHR] 2.72, 95% CI 0.43 – 17.22, p = 0.287). Thirty-day mortality was higher on univariate analysis for patients with LRSE versus those without (33% vs 10%, p = 0.021), although this difference was not significant when adjusted for confounders (aHR 3.01, 95% CI 0.72 – 12.69, p = 0.132). The Kaplan-Meier curve for 30-day mortality is presented in Figure 1 and the final regression models for 14- and 30-day mortality are presented in Supplemental Table 1 and Supplemental Table 2. Time to clearance of bacteremia The time to first negative blood culture was significantly longer for patients with LRSE bacteremia compared to those without (median 5 days vs 3 days; log-rank p = 0.029; hazard ratio [HR] 0.60; 95% CI 0.41-1.02, p=0.053). Linezolid resistance was the only term retained in the backwards stepwise Cox model, therefore, no adjusted analyses were performed. The Kaplan-Meier curve for clearance of bacteremia is presented in Figure 2. Discussion Although linezolid has been widely used for nearly 20 years with few reports of resistance in S. epidermidis, numerous reports of increasing numbers of LRSE in diverse clinical settings have recently been published [8-12, 17] At our hospital, we have found that 40% of S. epidermidis strains causing bacteremia in leukemia patients were linezolid-resistant, which is far higher than previously reported rates [18]. Moreover, our data show that leukemia patients with S. epidermidis bacteremia treated empirically with linezolid had significantly longer durations of bacteremia without Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript increased rates of ICU admission or short-term death when infected with linezolid-resistant versus linezolid-sensitive strains. Although this result may have been expected, it was not inevitable as in vitro susceptibilities do not always correlate with clinical response and S. epidermidis bacteremia may clear in the absence of specific treatment due to low virulence of the organism [19, 20]. While complications of S. epidermidis bacteremia are relatively rare, S. epidermidis is well-described to cause metastatic infections such as vertebral osteomyelitis, infective endocarditis, and prosthetic joint infections and we have observed multiple such complications in our patients [21]. Due to the uncommon nature of metastatic infections in patients with S. epidermidis, they were not specifically addressed in this study. Thus, further study is needed to assess the long-term implications of prolonged bacteremia with this organism. Previous studies have largely been unable to evaluate the significance of linezolid resistance in S. epidermidis due to the low incidence of linezolid-resistant isolates. The largest study to date of linezolid-resistance in staphylococci, performed in Italy, demonstrated that hospitalized patients with linezolid-resistant isolates were generally more acutely ill and had higher 30-day mortality in comparison to those with linezolid-sensitive strains, although the impact of empiric therapy was not directly assessed [13]. In contrast, patients in our study were relatively homogeneous with regards to both severity of illness and underlying comorbidities, allowing for a direct assessment of linezolid resistance on clinical outcomes in patients treated empirically with linezolid. In our study, both 14- and 30-day mortality were numerically higher among patients with LRSE, however, neither was statistically significant on adjusted analysis. When viewed alongside the persistent bacteremia experienced by patients with LRSE, S. epidermidis may have played some role in the observed increase i in mortality. We have previously reported that rates of LRSE at our institution correlate directly with linezolid utilization, with 13 defined daily doses (DDD) per 100 patient days serving as a potential threshold Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript for the emergence of resistance and linezolid use on our leukemia service consistently exceeded this threshold [5]. Furthermore, our group has recently identified that linezolid resistance in our institution is almost exclusively due to clonal spread of CC5 isolates harboring cfr and mutations in the L3 and L4 ribosomal proteins, with selection of linezolid resistance largely attributable to prior linezolid exposure [12]. Other groups worldwide have also reported the emergence and clonal spread of CC5 isolates in settings where linezolid is commonly used [8, 10, 22, 23]. In light of these data, both infection control and antimicrobial stewardship appear to play an important role in limiting the further spread of LRSE. Thus, given the adverse clinical impact of linezolid resistance in S. epidermidis that we have identified and the potential for S. epidermidis to serve as a reservoir for dissemination of cfr [24], interventions to limit the emergence of LRSE are warranted. Implementation of an antimicrobial stewardship program designed to optimize the use of linezolid has been shown to decrease the linezolid resistance rate in CoNS by 63% with no significant impact on patient safety [25]. Other stewardship interventions and infection control measures are supported by current guidelines and may be similarly effective in reducing the use of linezolid and clonal spread of LRSE [26]. Our study has some limitations, including its retrospective, single-center design. Ideally, prospective studies investigating long-term outcomes in patients with LRSE bacteremia would be performed, however, due to the relative infrequency of these outcomes, such a study is unlikely. As our study was focused on empiric treatment, we did not directly assess the impact of antimicrobial changes or the impact of catheter removal after identification of LRSE. Our inclusion criteria accounted for laboratory-defined criteria for a true infection, however, a full clinical assessment addressing whether these were true S. epidermidis infections was not performed but the high rates of persistent bacteremia that we observed strongly suggests that the majority of cases actually represented S. epidermidis bacteremia rather than blood culture contamination. Moreover, as all Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript patients were treated with linezolid empirically, it is likely that any selection bias resulting from this inclusion criteria would be minimal. Lastly, centers do not use linezolid as empiric therapy in leukemia patients due to concerns for cytopenias. However, as linezolid resistance is being increasingly reported worldwide, these findings are likely to be applicable to any center with high rates of empiric linezolid use. Conclusion Patients with LRSE bacteremia treated empirically with linezolid have persistent bacteremia and numerically increased mortality when compared patients with linezolid-susceptible infections. Implementation of an antimicrobial stewardship program to optimize linezolid usage may contribute to reducing the negative clinical impact of linezolid resistance amongst S. epidermidis. Funding No external funding was obtained in the completion of this work. Acknowledgements This work was presented, in part, as an oral presentation at IDWeek 2016 (Abstract #116; October 27, 2016; New Orleans, LA). References 1. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36(9): 1103-10. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 2. Lahoti A, Kantarjian H, Salahudeen AK, et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Cancer 2010; 116(17): 4063-8. 3. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis 2006; 42(5): 597-607. 4. Farrell DJ, Mendes RE, Ross JE, Jones RN. Linezolid surveillance program results for 2008 (LEADER Program for 2008). Diagn Microbiol Infect Dis 2009; 65(4): 392-403. 5. Mulanovich VE, Huband MD, McCurdy SP, et al. Emergence of linezolid-resistant coagulase- negative Staphylococcus in a cancer centre linked to increased linezolid utilization. J Antimicrob Chemother 2010; 65(9): 2001-4. 6. Lazaris A, Coleman DC, Kearns AM, et al. Novel multiresistance cfr plasmids in linezolid- resistant methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium (VRE) from a hospital outbreak: co-location of cfr and optrA in VRE. J Antimicrob Chemother 2017. 7. Morroni G, Brenciani A, Vincenzi C, et al. A clone of linezolid-resistant Staphylococcus epidermidis bearing the G2576T mutation is endemic in an Italian hospital. J Hosp Infect 2016; 94(2): 203-6. 8. Rodriguez-Lucas C, Fernandez J, Boga JA, et al. Nosocomial ventriculitis caused by a meticillin- and linezolid-resistant clone of Staphylococcus epidermidis in neurosurgical patients. J Hosp Infect 2018. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 9. Freitas AR, Dilek AR, Peixe L, Novais C. 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Int J Antimicrob Agents 2015; 45(3): 255-61. 14. Hill PC, Birch M, Chambers S, et al. Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality. Intern Med J 2001; 31(2): 97-103. 15. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42(2): 377-81. 16. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004; 159(7): 702-6. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 17. Layer F, Vourli S, Karavasilis V, et al. Dissemination of linezolid-dependent, linezolid-resistant Staphylococcus epidermidis clinical isolates belonging to CC5 in German hospitals. J Antimicrob Chemother 2018. 18. Flamm RK, Mendes RE, Hogan PA, Streit JM, Ross JE, Jones RN. Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014). Antimicrob Agents Chemother 2016; 60(4): 2273-80. 19. Rogers KL, Fey PD, Rupp ME. Coagulase-negative staphylococcal infections. Infect Dis Clin North Am 2009; 23(1): 73-98. 20. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis 2006; 42 Suppl 2: S82-9. 21. Otto M. Staphylococcus epidermidis--the 'accidental' pathogen. Nat Rev Microbiol 2009; 7(8): 555-67. 22. Wessels C, Strommenger B, Klare I, et al. Emergence and control of linezolid-resistant Staphylococcus epidermidis in an ICU of a German hospital. J Antimicrob Chemother 2018; 73(5): 1185-93. 23. Layer F, Vourli S, Karavasilis V, et al. Dissemination of linezolid-dependent, linezolid-resistant Staphylococcus epidermidis clinical isolates belonging to CC5 in German hospitals. J Antimicrob Chemother 2018; 73(5): 1181-4. 24. Cafini F, Nguyen le TT, Higashide M, Roman F, Prieto J, Morikawa K. Horizontal gene transmission of the cfr gene to MRSA and Enterococcus: role of Staphylococcus epidermidis as a reservoir and alternative pathway for the spread of linezolid resistance. J Antimicrob Chemother 2016; 71(3): 587-92. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 25. Garcia-Martinez L, Gracia-Ahulfinger I, Machuca I, et al. Impact of the PROVAUR stewardship programme on linezolid resistance in a tertiary university hospital: a before-and-after interventional study. J Antimicrob Chemother 2016. 26. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016; 62(10): e51-77. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 1. Cohort characteristics Characteristic Overall Linezolid- Linezolid- p value Resistant Susceptible 82 (100) 33 (40) 49 (60) Number of patients 60 (39 – 67) 58 (23 – 79) 62 (18 – 87) 0.505 Age, median (range) Male gender 43 (52) 16 (48) 27 (55) 0.654 Type of leukemia 0.353 AML 51 (62) 23 (70) 28 (57) Other 31 (38) 10 (30) 21 (43) 60 (73) 28 (85) 32 (65) 0.075 Salvage chemotherapy Previous HSCT 24 (30) 11 (33) 13 (27) 0.622 3 ¶ ANC < 500 cells/mm 65 (79) 32 (97) 33 (67) 0.001 Pitt bacteremia score, 0 (0 – 1) 1 (0 – 2) 0 (0 – 1) 0.053 median (IQR) Presence of CVC 76 (93) 30 (91) 46 (94) 0.681 Bacterial colony count from CVC 0.707 < 10 CFU/mL 7 (9) 2 (6) 5 (10) Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript > 10 CFU/mL 40 (49) 15 (45) 25 (51) Not quantified 35 (43) 16 (48) 19 (39) Removal of CVC within 72 hours 13 (17) 5 (17) 8 (17) 0.987 32 (39) 18 (55) 14 (29) 0.022 Hospital-onset All values n (%) unless otherwise specified AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; ANC – absolute neutrophil count; IQR – interquartile range; CVC – central venous catheter Ŧ ¶ Wilcoxon rank-sum test; Fisher’s exact test Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 2. Poisson regression model for the composite endpoint Unadjusted Model Adjusted Model Factor RR 95% CI p-value aRR 95% CI p-value 1.86 1.14 – 3.03 0.013 1.46 0.92 – 2.32 0.108 LRSE Age 1.00 0.99 – 1.02 0.620 -- -- -- Male gender 1.23 0.75 – 2.02 0.407 -- -- -- AML 2.13 1.11 – 4.08 0.023 1.84 0.96 – 3.49 0.064 Salvage 1.10 0.62 – 1.96 0.747 -- -- -- chemotherapy Prior HSCT 1.21 0.73 – 2.01 0.464 -- -- -- 1.74 0.79 – 3.85 0.169 -- -- -- Neutropenia Pitt Bacteremia 1.18 1.10 – 1.27 <0.001 1.09 1.00 – 1.18 0.040 score Presence of 0.87 0.37 – 2.0 0.744 -- -- -- CVC -- -- -- Bacterial colony Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript count from CVC <10 CFU (ref.) -- -- -- -- -- -- >10 CFU 0.88 0.43 – 1.79 0.715 -- -- -- Unknown 0.6 0.27 – 1.33 0.207 -- -- -- Hospital-onset 1.95 1.20 – 3.18 0.007 1.49 0.90 – 2.49 0.123 RR – risk ratio; aRR – adjusted risk ratio; CI – confidence interval; LRSE – linezolid-resistant Staphylococcus epidermidis; AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; CVC – central venous catheter; CFU – colony forming units Composite endpoint: persistent bacteremia, fever, intensive care unit (ICU) admission, or death within 3 days of index culture Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 3. Poisson regression models for persistent bacteremia at day 3 Unadjusted Model Adjusted Model Factor RR 95% CI p-value aRR 95% CI p-value 6.21 1.90 – 20.28 0.003 5.15 1.63 – 16.30 0.005 LRSE Age 1.00 0.98 – 1.02 0.924 1.03 1.00 – 1.05 0.021 Male gender 1.14 0.46 – 2.85 0.774 -- -- -- AML 8.52 1.17 – 62.16 0.035 7.17 1.53 – 33.57 0.012 Salvage 1.58 0.49 – 5.10 0.440 -- -- -- chemotherapy Prior HSCT 3.32 1.33 – 8.30 0.010 4.06 1.76 – 9.36 0.001 3.27 0.46 – 23.12 0.236 -- -- -- Neutropenia Pitt Bacteremia 1.32 1.19 – 1.52 <0.001 -- -- -- score Presence of 1.24 0.19 – 7.95 0.824 4.00 0.56 – 28.49 0.167 CVC -- -- -- Bacterial colony Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript count from CVC <10 CFU (ref.) -- -- -- -- -- -- >10 CFU 1.80 0.27 – 12.19 0.547 -- -- -- Unknown 1.09 0.15 – 8.07 0.930 -- -- -- Hospital-onset 1.88 0.76 – 4.64 0.173 -- -- -- RR – risk ratio; aRR – adjusted risk ratio; CI – confidence interval; LRSE – linezolid-resistant Staphylococcus epidermidis; AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; CVC – central venous catheter; CFU – colony forming units Limited to patients with one or more follow-up blood cultures (n = 74) Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Thirty-day mortality stratified by linezolid resistance status. Figure 2. Time to clearance of bacteremia stratified by linezolid resistance status. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Clinical outcomes associated with linezolid resistance in leukemia patients with linezolid-resistant Staphylococcus epidermidis bacteremia

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Abstract

Clinical outcomes associated with linezolid resistance in leukemia patients with linezolid-resistant Staphylococcus epidermidis bacteremia a a a b b Stephanie A. Folan ; Kayleigh R. Marx ; Frank P. Tverdek ; Issam Raad ; Victor E. Mulanovich , c b,d,e a,e* Jeffrey J. Tarrand ; Samuel A. Shelburne ; Samuel L. Aitken a – Division of Pharmacy; b – Department of Infectious Diseases, Infection Control, and Employee Health; c – Department of Laboratory Medicine; d – Department of Genomic Medicine; The University of Texas MD Anderson Cancer Center, Houston, TX; e – Center for Antimicrobial Resistance and Microbial Genomics UTHealth McGovern Medical School, Houston, TX *Person to whom correspondence should be addressed: Samuel L. Aitken, PharmD, BCPS (AQ-ID) Division of Pharmacy (Unit 0090) MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Phone: +1 (713) 745-3968 Fax: +1 (713) 792-5256 Email: SLAitken@mdanderson.org Keywords: Febrile neutropenia; catheter-related bloodstream infection; staphylococci; antimicrobial stewardship; hematologic malignancy © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Summary: Linezolid resistance is increasingly reported worldwide, but the clinical significance of linezolid resistance is unclear. We show that linezolid resistance is associated with prolonged bacteremia in leukemia patients with Staphylococcus epidermidis bacteremia treated empirically with linezolid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Background: Coagulase-negative staphylococci, including S. epidermidis, are the most common cause of bloodstream infection in cancer patients. Linezolid resistance is increasingly identified in S. epidermidis but whether such resistance alters the clinical course of S. epidermidis infections is unknown. The purpose of this study was to assess the clinical impact of linezolid resistance in leukemia patients with S. epidermidis bloodstream infection. Methods: This was a retrospective, single-center, cohort study of all adult leukemia patients with S. epidermidis bacteremia treated with empiric linezolid between 2012 and 2015. The primary endpoint was adverse clinical outcome on day three, defined as a composite of persistent bacteremia, fever, ICU admission, or death. Fourteen and 30-day mortality were also assessed. Results: Eighty-two unique leukemia patients with S. epidermidis were identified. Linezolid resistance was identified in 33/82 (40%). Patients with linezolid-resistant S. epidermidis were more significantly more likely to have persistent bacteremia (41% vs 7%; adjusted relative risk [aRR] 5.15, 95% CI 1.63 – 16.30; p =0.005), however, adverse short-term clinical outcomes overall were not more common among patients with linezolid-resistant S. epidermidis (61% vs 33%; aRR 1.46, 95% CI 0.92 – 2.32; p = 0.108). No differences were observed in 14- and 30-day mortality. Conclusion: Leukemia patients with linezolid-resistant S. epidermidis bacteremia who were treated with linezolid were significantly more likely to have persistent bacteremia compared to those with linezolid-sensitive isolates. Interventions to limit the clinical impact of linezolid resistant S. epidermidis are warranted. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Background Coagulase-negative Staphylococcus (CoNS), including Staphylococcus epidermidis, are the leading cause of catheter-related bloodstream infections (BSI) in the general hospital population and are responsible for 30% of BSI in patients with hematologic malignancy [1]. The use of linezolid for infections suspected or known to be caused by Gram-positive bacteria is increasing due to the rise in drug-resistant microorganisms and concerns for nephrotoxicity caused by vancomycin [2, 3]. Globally, approximately 2% of CoNS are resistant to linezolid, however resistance rates may be higher in institutions with high rates of linezolid usage [4, 5]. Clonal dissemination of linezolid-resistant S. epidermidis (LRSE) is increasingly reported in diverse settings worldwide although prior studies have not assessed the clinical impact of LRSE [6-11]. At our institution, LRSE occurs nearly exclusively in patients with leukemia and is associated with epidemic spread of a clonal complex 5 (CC5) strain with a cfr-harboring plasmid [5, 12]. A case-control study performed in Italy identified higher 30-day mortality in patients with linezolid-resistant compared to linezolid-susceptible staphylococci, however, no information was provided on the antimicrobials used for the treatment of these infections [13]. To our knowledge, no prior studies have examined mortality in relation to linezolid being used as treatment for LRSE BSI. Thus, we sought to test the hypotheses that LRSE bacteremia empirically treated with linezolid would have worse clinical outcomes in comparison to patients infected by linezolid-sensitive strains. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Methods Study design We performed a retrospective cohort study of adult patients (aged ≥ 18 years) with leukemia (including acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], and others) or the myelodysplastic syndrome (MDS) and laboratory-confirmed S. epidermidis bacteremia who received empiric linezolid treatment at the University of Texas MD Anderson Cancer Center from July 1, 2012 to July 22, 2015. Patients with prior hematopoietic stem cell transplant (HSCT) were included if in relapse at the time of S. epidermidis bacteremia. At our institution, CoNS are not routinely identified to the species level unless laboratory-defined criteria suggestive of true infection (i.e., culture positivity from more than one blood draw site or >10 colony forming units [CFU] from a single site) are met. To further limit the reporting of contaminated blood cultures, cultures positive for <10 CFU of CoNS from a single site are not reported to the treating providers. CoNS that were not identified to the species level or CoNS species other than S. epidermidis were not included. Linezolid susceptibility was determined via Vitek 2 (bioMérieux, Marcy-L’Étoile, France) with a minimum inhibitory concentration (MIC) >4µg/mL considered resistant per current CLSI standards (https://clsi.org/standards/products/microbiology/documents/m100/); resistant isolates were confirmed by Etest (bioMérieux) per standard protocol in the clinical microbiology laboratory. Twelve isolates were missing data for the confirmatory Etest; these isolates were considered to be resistant based on prior experience demonstrating 100% concordance between Vitek 2 susceptibility resting and laboratory-confirmed resistance [12]. Patients were identified through microbiology laboratory records, and clinical information was collected from the electronic health record. Patients with more than one occurrence of S. epidermidis bacteremia were included only once. Endpoints and study definitions The primary endpoint was a composite of adverse short-term outcomes on day 3 after the index culture, defined as persistent bacteremia (isolation of S. epidermidis from blood > 3 days after the Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript index culture without an intervening negative blood culture), persistent fever (temperature ≥ 38°C on day 3), ICU admission, or death, each by day 3 following the index culture. Day 3 was chosen as this would approximate the time at which organism identification and susceptibility would be available and would therefore more closely reflect the impact of empiric therapy. As mortality due to this organism was expected to be low, 14-day and 30-day mortality were considered as secondary outcomes. Other secondary outcomes consisted of individual components of the composite endpoint and time to blood culture clearance (i.e., first recorded negative blood culture) within 7 days. Assessment of persistent bacteremia and time to blood culture clearance was limited to patients in which at least one followup blood culture was obtained. Empiric treatment with linezolid was defined as at least one dose of linezolid within one day of the date the positive index blood culture was obtained. Salvage chemotherapy was considered to be any chemotherapy administered after failed primary induction, relapsed disease, and/or enrollment in a clinical trial for either of these reasons. Severity of illness was assessed at the time of the index blood culture using the Pitt bacteremia score, a validated scoring system based on mental status, vital signs, requirement for mechanical ventilation, and recent cardiac arrest [14]. This protocol was approved by the Institutional Review Board at MD Anderson Cancer Center with a waiver of informed consent. Data was collected via electronic chart review and stored using REDCap (Vanderbilt University, Nashville, TN) [15]. Statistical analysis Baseline characteristics were compared using the Wilcoxon rank-sum and Fisher’s exact test, with all comparisons made between patients with linezolid-resistant and linezolid-susceptible isolates. After univariate analysis, multivariate Poisson regression with robust variance estimates, adjusting for clinically relevant confounders, was performed for the primary composite endpoint and persistent bacteremia. Poisson regression was chosen over logistic regression as the dependent Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript variables of interest had incidences greater than 10%, invalidating the assumption that the odds ratio approximates the relative risk [16]. No multivariate analyses were performed for other components of the composite endpoint as these were infrequent and not amenable to multivariate analysis. Fourteen and 30-day mortality and time to clearance of bacteremia were assessed using multivariate Cox proportional hazards modelling and Kaplan-Meier curves. As blood cultures were not obtained on a daily basis for most patients, the first date of a documented negative culture was considered to be the first negative day for the survival analysis. Patients with no follow-up cultures performed were removed from the time-to-event analysis for clearance of bacteremia. The proportional hazards assumptions were verified by visual assessment of the scaled Schoenfeld residuals. All multivariate models were constructed using a backwards stepwise approach, incorporating all variables with a univariate p-value < 0.2 and removing those with the largest p- value sequentially until only variables with a p-value < 0.2 remained. Removal of the central venous catheter (CVC) was not included in multivariate models to avoid adjusting for a downstream consequence of persistent bacteremia. Statistical analyses were performed via STATA v14.1 (StataCorp LP, College Station, TX). Results Cohort characteristics Eighty-two unique patients (median age 52 years, range 39 – 67; 52% male) were included in the study. Overall, 33 (40%) of S. epidermidis isolates were LRSE, with an MIC and MIC of 2 mcg/mL 50 90 and > 256 µg/mL, respectively. Among the 33 resistant isolates, 30/33 (91%) displayed high-level resistance with MICs of > 256 µg/mL. There were no statistically significant differences in clinical characteristics between patients with linezolid-resistant and linezolid-susceptible isolates (Table 1), except for neutropenia (absolute neutrophil count <500 cells/mm ) at the time of first positive blood culture (97% vs 67%, respectively; p=0.001) and nosocomial onset (55% vs 29%, Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript respectively; p=0.022). The majority of patients had acute myeloid leukemia (62%), followed by acute lymphoblastic leukemia (24%). In general patients had been extensively treated for their leukemia, with 73% receiving salvage chemotherapy and 29% having previously received an allogeneic hematopoietic stem cell transplant. However, the study population was not acutely ill, as reflected in the low median Pitt bacteremia score (0, interquartile range [IQR] 0-1). Most patients had a CVC (93%) and removal of the CVC within three days of bacteremia onset was similarly infrequent among patients with and without linezolid-resistant isolates (17% in each group, p = 0.987).. Outcomes assessment Composite outcome Seventy-four patients (90%) had at least one follow-up blood culture. Persistent bacteremia was significantly more common among patients with LRSE (41% vs 7%, p = 0.001) and remained significantly more common after adjustment for confounders (adjusted relative risk [aRR] 3.97, 95% confidence interval [CI] 1.23 – 12.86, p = 0.021).. No significant differences were observed for other components of the composite endpoint, including persistent fever (27% vs 24%, p = 0.801), ICU admission (15% vs 10%, p = 0.51), and death by day 3 (3% vs 2%, p = 1.000). Overall, the composite endpoint was significantly more frequent in patients with LRSE as compared to those with linezolid-susceptible bacteremia in univariate analysis (61% vs 33%, p = 0.023), however, no significant difference was observed after adjustment for other confounders (aRR 1.46; 95% confidence interval CI 0.92 – 2.32, p=0.108). Full Poisson regression models for the composite endpoint and persistent bacteremia are shown in Table 2 and Table 3. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 14- and 30-day mortality All deaths occurred among patients receiving salvage chemotherapy, therefore, mortality analysis was limited to this subgroup (n = 60). A trend towards increased unadjusted and adjusted mortality at day 14 was observed for patients with LRSE versus those without (21% vs 8%; adjusted hazard ratio [aHR] 2.72, 95% CI 0.43 – 17.22, p = 0.287). Thirty-day mortality was higher on univariate analysis for patients with LRSE versus those without (33% vs 10%, p = 0.021), although this difference was not significant when adjusted for confounders (aHR 3.01, 95% CI 0.72 – 12.69, p = 0.132). The Kaplan-Meier curve for 30-day mortality is presented in Figure 1 and the final regression models for 14- and 30-day mortality are presented in Supplemental Table 1 and Supplemental Table 2. Time to clearance of bacteremia The time to first negative blood culture was significantly longer for patients with LRSE bacteremia compared to those without (median 5 days vs 3 days; log-rank p = 0.029; hazard ratio [HR] 0.60; 95% CI 0.41-1.02, p=0.053). Linezolid resistance was the only term retained in the backwards stepwise Cox model, therefore, no adjusted analyses were performed. The Kaplan-Meier curve for clearance of bacteremia is presented in Figure 2. Discussion Although linezolid has been widely used for nearly 20 years with few reports of resistance in S. epidermidis, numerous reports of increasing numbers of LRSE in diverse clinical settings have recently been published [8-12, 17] At our hospital, we have found that 40% of S. epidermidis strains causing bacteremia in leukemia patients were linezolid-resistant, which is far higher than previously reported rates [18]. Moreover, our data show that leukemia patients with S. epidermidis bacteremia treated empirically with linezolid had significantly longer durations of bacteremia without Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript increased rates of ICU admission or short-term death when infected with linezolid-resistant versus linezolid-sensitive strains. Although this result may have been expected, it was not inevitable as in vitro susceptibilities do not always correlate with clinical response and S. epidermidis bacteremia may clear in the absence of specific treatment due to low virulence of the organism [19, 20]. While complications of S. epidermidis bacteremia are relatively rare, S. epidermidis is well-described to cause metastatic infections such as vertebral osteomyelitis, infective endocarditis, and prosthetic joint infections and we have observed multiple such complications in our patients [21]. Due to the uncommon nature of metastatic infections in patients with S. epidermidis, they were not specifically addressed in this study. Thus, further study is needed to assess the long-term implications of prolonged bacteremia with this organism. Previous studies have largely been unable to evaluate the significance of linezolid resistance in S. epidermidis due to the low incidence of linezolid-resistant isolates. The largest study to date of linezolid-resistance in staphylococci, performed in Italy, demonstrated that hospitalized patients with linezolid-resistant isolates were generally more acutely ill and had higher 30-day mortality in comparison to those with linezolid-sensitive strains, although the impact of empiric therapy was not directly assessed [13]. In contrast, patients in our study were relatively homogeneous with regards to both severity of illness and underlying comorbidities, allowing for a direct assessment of linezolid resistance on clinical outcomes in patients treated empirically with linezolid. In our study, both 14- and 30-day mortality were numerically higher among patients with LRSE, however, neither was statistically significant on adjusted analysis. When viewed alongside the persistent bacteremia experienced by patients with LRSE, S. epidermidis may have played some role in the observed increase i in mortality. We have previously reported that rates of LRSE at our institution correlate directly with linezolid utilization, with 13 defined daily doses (DDD) per 100 patient days serving as a potential threshold Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript for the emergence of resistance and linezolid use on our leukemia service consistently exceeded this threshold [5]. Furthermore, our group has recently identified that linezolid resistance in our institution is almost exclusively due to clonal spread of CC5 isolates harboring cfr and mutations in the L3 and L4 ribosomal proteins, with selection of linezolid resistance largely attributable to prior linezolid exposure [12]. Other groups worldwide have also reported the emergence and clonal spread of CC5 isolates in settings where linezolid is commonly used [8, 10, 22, 23]. In light of these data, both infection control and antimicrobial stewardship appear to play an important role in limiting the further spread of LRSE. Thus, given the adverse clinical impact of linezolid resistance in S. epidermidis that we have identified and the potential for S. epidermidis to serve as a reservoir for dissemination of cfr [24], interventions to limit the emergence of LRSE are warranted. Implementation of an antimicrobial stewardship program designed to optimize the use of linezolid has been shown to decrease the linezolid resistance rate in CoNS by 63% with no significant impact on patient safety [25]. Other stewardship interventions and infection control measures are supported by current guidelines and may be similarly effective in reducing the use of linezolid and clonal spread of LRSE [26]. Our study has some limitations, including its retrospective, single-center design. Ideally, prospective studies investigating long-term outcomes in patients with LRSE bacteremia would be performed, however, due to the relative infrequency of these outcomes, such a study is unlikely. As our study was focused on empiric treatment, we did not directly assess the impact of antimicrobial changes or the impact of catheter removal after identification of LRSE. Our inclusion criteria accounted for laboratory-defined criteria for a true infection, however, a full clinical assessment addressing whether these were true S. epidermidis infections was not performed but the high rates of persistent bacteremia that we observed strongly suggests that the majority of cases actually represented S. epidermidis bacteremia rather than blood culture contamination. Moreover, as all Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript patients were treated with linezolid empirically, it is likely that any selection bias resulting from this inclusion criteria would be minimal. Lastly, centers do not use linezolid as empiric therapy in leukemia patients due to concerns for cytopenias. However, as linezolid resistance is being increasingly reported worldwide, these findings are likely to be applicable to any center with high rates of empiric linezolid use. Conclusion Patients with LRSE bacteremia treated empirically with linezolid have persistent bacteremia and numerically increased mortality when compared patients with linezolid-susceptible infections. Implementation of an antimicrobial stewardship program to optimize linezolid usage may contribute to reducing the negative clinical impact of linezolid resistance amongst S. epidermidis. Funding No external funding was obtained in the completion of this work. Acknowledgements This work was presented, in part, as an oral presentation at IDWeek 2016 (Abstract #116; October 27, 2016; New Orleans, LA). References 1. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36(9): 1103-10. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 2. Lahoti A, Kantarjian H, Salahudeen AK, et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Cancer 2010; 116(17): 4063-8. 3. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis 2006; 42(5): 597-607. 4. Farrell DJ, Mendes RE, Ross JE, Jones RN. Linezolid surveillance program results for 2008 (LEADER Program for 2008). Diagn Microbiol Infect Dis 2009; 65(4): 392-403. 5. Mulanovich VE, Huband MD, McCurdy SP, et al. Emergence of linezolid-resistant coagulase- negative Staphylococcus in a cancer centre linked to increased linezolid utilization. J Antimicrob Chemother 2010; 65(9): 2001-4. 6. Lazaris A, Coleman DC, Kearns AM, et al. Novel multiresistance cfr plasmids in linezolid- resistant methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium (VRE) from a hospital outbreak: co-location of cfr and optrA in VRE. J Antimicrob Chemother 2017. 7. Morroni G, Brenciani A, Vincenzi C, et al. A clone of linezolid-resistant Staphylococcus epidermidis bearing the G2576T mutation is endemic in an Italian hospital. J Hosp Infect 2016; 94(2): 203-6. 8. Rodriguez-Lucas C, Fernandez J, Boga JA, et al. Nosocomial ventriculitis caused by a meticillin- and linezolid-resistant clone of Staphylococcus epidermidis in neurosurgical patients. J Hosp Infect 2018. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 9. Freitas AR, Dilek AR, Peixe L, Novais C. Dissemination of Staphylococcus epidermidis ST22 With Stable, High-Level Resistance to Linezolid and Tedizolid in the Greek-Turkish Region (2008-2016). Infect Control Hosp Epidemiol 2018; 39(4): 492-4. 10. Dortet L, Glaser P, Kassis-Chikhani N, et al. Long-lasting successful dissemination of resistance to oxazolidinones in MDR Staphylococcus epidermidis clinical isolates in a tertiary care hospital in France. J Antimicrob Chemother 2018; 73(1): 41-51. 11. Wessels C, Strommenger B, Klare I, et al. Emergence and control of linezolid-resistant Staphylococcus epidermidis in an ICU of a German hospital. J Antimicrob Chemother 2018. 12. Li X, Arias CA, Aitken SL, et al. Clonal Emergence of Invasive Multidrug-Resistant Staphylococcus epidermidis Deconvoluted via a Combination of Whole-Genome Sequencing and Microbiome Analyses. Clin Infect Dis 2018. 13. Russo A, Campanile F, Falcone M, et al. Linezolid-resistant staphylococcal bacteraemia: A multicentre case-case-control study in Italy. Int J Antimicrob Agents 2015; 45(3): 255-61. 14. Hill PC, Birch M, Chambers S, et al. Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality. Intern Med J 2001; 31(2): 97-103. 15. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42(2): 377-81. 16. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004; 159(7): 702-6. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 17. Layer F, Vourli S, Karavasilis V, et al. Dissemination of linezolid-dependent, linezolid-resistant Staphylococcus epidermidis clinical isolates belonging to CC5 in German hospitals. J Antimicrob Chemother 2018. 18. Flamm RK, Mendes RE, Hogan PA, Streit JM, Ross JE, Jones RN. Linezolid Surveillance Results for the United States (LEADER Surveillance Program 2014). Antimicrob Agents Chemother 2016; 60(4): 2273-80. 19. Rogers KL, Fey PD, Rupp ME. Coagulase-negative staphylococcal infections. Infect Dis Clin North Am 2009; 23(1): 73-98. 20. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis 2006; 42 Suppl 2: S82-9. 21. Otto M. Staphylococcus epidermidis--the 'accidental' pathogen. Nat Rev Microbiol 2009; 7(8): 555-67. 22. Wessels C, Strommenger B, Klare I, et al. Emergence and control of linezolid-resistant Staphylococcus epidermidis in an ICU of a German hospital. J Antimicrob Chemother 2018; 73(5): 1185-93. 23. Layer F, Vourli S, Karavasilis V, et al. Dissemination of linezolid-dependent, linezolid-resistant Staphylococcus epidermidis clinical isolates belonging to CC5 in German hospitals. J Antimicrob Chemother 2018; 73(5): 1181-4. 24. Cafini F, Nguyen le TT, Higashide M, Roman F, Prieto J, Morikawa K. Horizontal gene transmission of the cfr gene to MRSA and Enterococcus: role of Staphylococcus epidermidis as a reservoir and alternative pathway for the spread of linezolid resistance. J Antimicrob Chemother 2016; 71(3): 587-92. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 25. Garcia-Martinez L, Gracia-Ahulfinger I, Machuca I, et al. Impact of the PROVAUR stewardship programme on linezolid resistance in a tertiary university hospital: a before-and-after interventional study. J Antimicrob Chemother 2016. 26. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis 2016; 62(10): e51-77. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 1. Cohort characteristics Characteristic Overall Linezolid- Linezolid- p value Resistant Susceptible 82 (100) 33 (40) 49 (60) Number of patients 60 (39 – 67) 58 (23 – 79) 62 (18 – 87) 0.505 Age, median (range) Male gender 43 (52) 16 (48) 27 (55) 0.654 Type of leukemia 0.353 AML 51 (62) 23 (70) 28 (57) Other 31 (38) 10 (30) 21 (43) 60 (73) 28 (85) 32 (65) 0.075 Salvage chemotherapy Previous HSCT 24 (30) 11 (33) 13 (27) 0.622 3 ¶ ANC < 500 cells/mm 65 (79) 32 (97) 33 (67) 0.001 Pitt bacteremia score, 0 (0 – 1) 1 (0 – 2) 0 (0 – 1) 0.053 median (IQR) Presence of CVC 76 (93) 30 (91) 46 (94) 0.681 Bacterial colony count from CVC 0.707 < 10 CFU/mL 7 (9) 2 (6) 5 (10) Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript > 10 CFU/mL 40 (49) 15 (45) 25 (51) Not quantified 35 (43) 16 (48) 19 (39) Removal of CVC within 72 hours 13 (17) 5 (17) 8 (17) 0.987 32 (39) 18 (55) 14 (29) 0.022 Hospital-onset All values n (%) unless otherwise specified AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; ANC – absolute neutrophil count; IQR – interquartile range; CVC – central venous catheter Ŧ ¶ Wilcoxon rank-sum test; Fisher’s exact test Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 2. Poisson regression model for the composite endpoint Unadjusted Model Adjusted Model Factor RR 95% CI p-value aRR 95% CI p-value 1.86 1.14 – 3.03 0.013 1.46 0.92 – 2.32 0.108 LRSE Age 1.00 0.99 – 1.02 0.620 -- -- -- Male gender 1.23 0.75 – 2.02 0.407 -- -- -- AML 2.13 1.11 – 4.08 0.023 1.84 0.96 – 3.49 0.064 Salvage 1.10 0.62 – 1.96 0.747 -- -- -- chemotherapy Prior HSCT 1.21 0.73 – 2.01 0.464 -- -- -- 1.74 0.79 – 3.85 0.169 -- -- -- Neutropenia Pitt Bacteremia 1.18 1.10 – 1.27 <0.001 1.09 1.00 – 1.18 0.040 score Presence of 0.87 0.37 – 2.0 0.744 -- -- -- CVC -- -- -- Bacterial colony Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript count from CVC <10 CFU (ref.) -- -- -- -- -- -- >10 CFU 0.88 0.43 – 1.79 0.715 -- -- -- Unknown 0.6 0.27 – 1.33 0.207 -- -- -- Hospital-onset 1.95 1.20 – 3.18 0.007 1.49 0.90 – 2.49 0.123 RR – risk ratio; aRR – adjusted risk ratio; CI – confidence interval; LRSE – linezolid-resistant Staphylococcus epidermidis; AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; CVC – central venous catheter; CFU – colony forming units Composite endpoint: persistent bacteremia, fever, intensive care unit (ICU) admission, or death within 3 days of index culture Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 3. Poisson regression models for persistent bacteremia at day 3 Unadjusted Model Adjusted Model Factor RR 95% CI p-value aRR 95% CI p-value 6.21 1.90 – 20.28 0.003 5.15 1.63 – 16.30 0.005 LRSE Age 1.00 0.98 – 1.02 0.924 1.03 1.00 – 1.05 0.021 Male gender 1.14 0.46 – 2.85 0.774 -- -- -- AML 8.52 1.17 – 62.16 0.035 7.17 1.53 – 33.57 0.012 Salvage 1.58 0.49 – 5.10 0.440 -- -- -- chemotherapy Prior HSCT 3.32 1.33 – 8.30 0.010 4.06 1.76 – 9.36 0.001 3.27 0.46 – 23.12 0.236 -- -- -- Neutropenia Pitt Bacteremia 1.32 1.19 – 1.52 <0.001 -- -- -- score Presence of 1.24 0.19 – 7.95 0.824 4.00 0.56 – 28.49 0.167 CVC -- -- -- Bacterial colony Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript count from CVC <10 CFU (ref.) -- -- -- -- -- -- >10 CFU 1.80 0.27 – 12.19 0.547 -- -- -- Unknown 1.09 0.15 – 8.07 0.930 -- -- -- Hospital-onset 1.88 0.76 – 4.64 0.173 -- -- -- RR – risk ratio; aRR – adjusted risk ratio; CI – confidence interval; LRSE – linezolid-resistant Staphylococcus epidermidis; AML – acute myeloid leukemia; HSCT – hematopoietic stem cell transplant; CVC – central venous catheter; CFU – colony forming units Limited to patients with one or more follow-up blood cultures (n = 74) Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Thirty-day mortality stratified by linezolid resistance status. Figure 2. Time to clearance of bacteremia stratified by linezolid resistance status. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy167/5053096 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Jul 13, 2018

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