Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections

Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial... Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections Sarah C.J. JORGENSEN 1,2 Trang D. TRINH 1,3 Evan J. ZASOWSKI Abdalhamid M. LAGNF Sahil BHATIA Sarah M. MELVIN Molly E. STEED Samuel P. SIMON 6,7 Sandra J. ESTRADA 1,8 Taylor MORRISETTE Kimberly C. CLAEYS Joshua R. ROSENBERG 1,10 Susan L. DAVIS © The Author(s) 2019. 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 © The Author(s) 2019. 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 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 1,11,12 Michael J. RYBAK 1. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA 2. Medication Outcomes Center, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA 3. Department of Clinical Sciences, College of Pharmacy, Touro University California, Vallejo, CA 4. Department of Pharmacy Practice, School of Pharmacy, University of Kansas, Kansas City, KS 5. Brooklyn Hospital, Brooklyn, NY 6. Department of Pharmacy, Lee Health, Fort Myers, FL 7. T2 Biosystems Inc, Lexington, MA 8. Department of Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States 9. Department of Pharmacy Practice, School of Pharmacy, University of Maryland, Baltimore, MD 10. Department of Pharmacy, Henry Ford Hospital, Detroit, MI 11. Department of Medicine, Wayne State University, Detroit, MI 12. Department of Pharmacy, Detroit Medical Center, Detroit, MI Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Corresponding Author Michael J. Rybak Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University 259 Mack Ave., Detroit, MI, USA, 48201 Phone: 313-577-4376 Fax: 313-577-9310 Email m.rybak@wayne.edu Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Abstract Objective To describe the clinical characteristics, microbiology and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant gram-negative (MDR-GN) infections. Methods Multicenter, retrospective cohort study at six medical centers in the U.S. between 2015 and 2019. Adult patients who received CZA (≥72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure and/or failure to resolve or improve signs or symptoms of infection on CZA. Results In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp. were isolated from 117(57.6%) and 63(31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%) and intra-abdominal (18.7%). Blood cultures were positive in 22(10.8%) patients. Clinical failure, 30-day mortality and 30-day recurrence occurred in 59(29.1%), 35(17.2%) and 12(5.9%) patients, respectively. On therapy CZA resistance developed in one of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (aOR 2.270, 95% CI 1.115-4.620 and aOR 1.234, 95% CI 1.118-1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR 0.409 95% CI 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (ten acute kidney injury, three Clostridioides difficile infection, two rash and one each gastrointestinal intolerance and neutropenia) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Conclusions CZA is being used to treat a range of MDR-GN infections including Pseudomonas spp. as well as CRE. Keywords Ceftazidime-avibactam, carbapenem-resistant Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Introduction Multidrug-resistant (MDR) gram-negative bacteria are a pressing infectious disease 1, 2 challenge. Carbapenems have served as the antibiotics of choice for infections caused by these pathogens for decades. However, the emergence and spread of carbapenemases threatens their utility as our last line of defense against MDR bacteria. The predominant carbapenemase in the United States is Klebsiella pneumoniae carbapenemase (KPC), an Ambler class A enzyme that hydrolyses nearly all currently available beta‐lactams. Bacteria that harbor blaKPC often carry other genes that encode resistance to a wide array of other antibiotic classes, posing a serious treatment 2, 3 challenge. Until recently, the only remaining antibiotics with preserved in vitro activity against 4-6 MDR strains were limited by unfavorable pharmacokinetic properties and/or toxicity. The high morbidity and mortality associated with infections caused by MDR gram-negative bacteria is partly due to the paucity of safe and effective treatment options, attesting to the need for continued antibiotic development. Ceftazidime-avibactam (CZA) is a combination antimicrobial consisting of an established antipseudomonal cephalosporin and a novel non-beta-lactam (diazabicyclooctane) beta-lactamase inhibitor. Avibactam protects ceftazidime from hydrolysis by Ambler class A and some class D carbapenemases. In surveillance studies, CZA has demonstrated in vitro activity against 8, 9 carbapenem-resistant Enterobatceriaceae (CRE) and MDR Pseudomonas aeruginosa. Real-world Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 experience with CZA for the treatment of CRE infections is slowly accumulating but data on its use 10-16 for other MDR gram-negative pathogens including P. aeruginosa remains limited. We sought to add to this data and describe the clinical characteristics, microbiology and outcomes of patients treated with CZA for a range of MDR gram-negative bacterial pathogens. Methods Study design and population This was a multicenter, retrospective, observational cohort study conducted at six geographically diverse academic medical centers in the U.S. between 2015 and 2019. Inclusion criteria were: 1) age ≥ 18 years and 2) receipt of ≥ 72 hours of CZA. For each patient, only the initial CZA treatment course during the study period was included. Ethics Approval was obtained from each participating center’s Institutional Review Board with a waiver for informed consent. Data collection and study definitions Pharmacy records were screened for all patients who received at least one dose of CZA during the study period. For eligible patients, demographic, clinical, microbiological and treatment data were extracted from the electronic medical record and entered into a secure data collection form. Bacterial identification and antibiotic susceptibilities were performed at each center according to standard procedures. CZA susceptibility was determined using disk diffusion or gradient strips, where available. CRE was defined by current U.S. Centers for Disease Control and Prevention (CDC) criteria. Infection onset was considered to be when the index culture was collected. Sources of infection were based on the treating physician’s notes and available clinical, microbiological and diagnostic data. The infection was classified as hospital-acquired if the index culture was obtained Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 greater than 48 hours after admission. Comorbidity burden was quantified using the Charlson 18 19 Comorbidity score. Severity of illness at infection onset was quantified using the SOFA score. CZA was administered as a standard dose of 2.5g IV every eight hours with dose adjustments based on estimate creatinine clearance (Cockroft Gault equation) according to the manufacturer’s recommendations. For the purposes of this study, CZA combination therapy was defined as the receipt of a concomitant gram-negative targeted antibiotic for ≥ 48 hours with CZA. Receipt of metronidazole was described separately. Microbiological failure was defined as infection recurrence with the same organism as isolated from the index culture after seven days of CZA therapy to the end of follow-up plus signs and symptoms of infection. Data were collected for up to 30 days following discharge (i.e. from health system outpatient clinics, rehabilitation centers, emergency departments and hospital re-admissions where available). Clinical failure was defined as a composite of all-cause 30-day mortality, microbiological failure and/or failure to resolve or improve signs and symptoms of infections during CZA therapy. Acute kidney injury (AKI) was evaluated in patients not receiving hemodialysis at the time of CZA initiation and was defined as a serum creatinine increase of ≥ 0.5 mg/dL or 50% from baseline on two consecutive measurements while on CZA and up to 72 hours following the last dose. Statistical analysis: Baseline characteristics of the overall cohort and in the CRE and Pseudomonas spp. subgroups were evaluated using descriptive statistics; discrete data were reported as counts and percentages and continuous data were reported as medians and interquartile ranges (IQR). Multivariable logistic regression analysis was performed to identify independent predictors of clinical failure. Since baseline characteristics, management and outcomes were similar in the overall cohort and the CRE and Pseudomonas spp. subgroups, this analysis was conducted using the overall cohort. Clinically relevant variables were selected for model entry based on bivariate comparisons (P < 0.2) and biological plausibility. Some variables were collapsed into single composite variables when the Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 number of patients in subgroups was too small to allow for meaningful analysis. The selected model was simplified based on the Akaike Information Criterion (AIC) in backward fashion. Multicollinearity of candidate regression models was assessed via the variance inflation factor, with values less than three considered acceptable. Secondary outcomes of interest included individual components of the composite outcome, discharge disposition, emergence of CZA resistance during treatment and hospital length of stay. Safety outcomes included AKI, dermatological reactions, cytopenias, central nervous system disturbances, gastrointestinal intolerance, and Clostridioides difficile-associated diarrhea. All analyses were performed using SPSS Statistics version 24.0 (IBM corp., Armonk, NY) and SAS 9.4 Statistical Software (SAS Institute Inc., Cary, NC). A two-tailed P value less than 0.05 was considered statistically significant. Results: Patient characteristics In total, 203 patients met study inclusion criteria and were evaluated. A complete description of patient baseline demographic and clinical characteristics are displayed in Table 1. Overall, the study cohort had a median age of 62 (IQR 49, 72) years with a high burden of medical comorbidity (median Charlson Comorbidity score 4 IQR 2, 6). Nearly half (93, 45.8%) of patients resided in a skilled nursing facility prior to admission or were transferred from an outside hospital and the majority of patients had a recent (90 day) history of hospitalization or systemic antibiotic exposure (151, 74.4% and 157, 77.3%, respectively). Many patients had a high severity of illness at infection onset with 102 (50.2%) residing in the ICU and a median (IQR) SOFA score of 5 (2, 8). Baseline characteristic of patients with CRE or Pseudomonas spp. infections were similar (Table 1). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Infection characteristics The majority of infections (117, 57.6%) were hospital-acquired with the median (IQR) time from admission to infection onset of 3 (2, 16) days. The most common infection sources were respiratory tract (76, 37.4%), followed by urinary tract (40, 19.7%), intra-abdominal (38, 18.7%), skin and soft tissue (18, 8.9%) and osteoarticular (14, 6.9%) (Table 2). Blood cultures were positive in 22 (10.8%) patients. CRE was isolated from 117 (57.6%) of culture specimens. Most CRE were K. pneumoniae (74/117, 63.2%), followed by E. coli (17/117, 14.5%) and Enterobacter spp. (15/117, 12.8%). Among the 50 carbapenem-resistant K. pneumoniae isolates tested, 48 (96.0%) were susceptible to CZA. One resistant isolate (CZA MIC > 256 mg/L) harbored both NDM and OXA carbapenemases. The mechanism of resistance in the second isolate is currently unknown. CZA was used to treat 63 patients with Pseudomonas spp. infections. The majority of Pseudomonas spp. infections had a respiratory tract source (38, 60.3%). Among the P. aeruginosa isolates for which the CZA susceptibility testing was performed (n=27), 25 (92.6%) were susceptible. One isolate demonstrated intermediate CZA susceptibility (zone diameter 18 mm) and a second was CZA resistant (MIC > 256 mg/L, positive for NDM and OXA carbapenemases). Of 40 P.aeruginosa isolates tested, 21 (52.5%) were susceptible to ceftazidime itself. The most common reason for the use of CZA in these patients was co-infection with CRE (n = 11) and cefepime resistance or failure in hospitals that did not carry ceftazidime on the formulary (n = 6). K. pneumoniae and P. aeruginosa antibiograms are shown in Supplementary Appendix 1. Infection management A summary of infection management is shown in Table 3. Overall 199 (98.0%) and 58 (28.6%) patients received an infectious disease or surgical consult, respectively and source control (e.g. line removal, abscess drainage) was pursued in 54 (26.6%) patients. The median time from culture collection to CZA initiation was 85 (42, 146) hours. Approximately one in four (54, 26.6%) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 patients received in vitro active antibiotic therapy prior to CZA with an overall median time to active antibiotic therapy of 55 (7, 102) hours. The most commonly used active agents prior to CZA were aminoglycosides (18/54, 33.3%). The CZA dose was renally adjusted in 92 (45.3%) patients. Eleven of these patients did not require dose adjustment based estimated CrCl > 50 mL/min at the start of CZA. Combination IV antibiotic therapy was used 68 (33.5%) patients, most commonly with an aminoglycoside (21, 10.3%), colistin / polymyxin B (17, 8.4%) or tigecycline (16, 7.9%). Three of 38 patients (7.9%) with an intra-abdominal infection received concomitant metronidazole. Inhaled antibiotics (tobramycin or colistin) were used in 19 of 76 patients (25.0%) with a respiratory tract infection. The median duration of inpatient CZA was 9 (6, 16) days. Outcomes Patient outcomes are displayed in Table 4. As shown, outcomes were similar in patients with CRE and Pseudomonas spp. infections. Overall, composite clinical failure and 30-day mortality occurred in 59 (29.1%) and 35 (17.2%) patients, respectively. Among patients originally admitted from home (n = 101), 29 (28.7%) and 10 (9.9%) required new nursing home placement or inpatient rehabilitation following discharge, respectively. The highest rates of clinical failure and 30-day mortality were recorded in patients with primary bacteremia (7/10, 70.0% and 4/10, 40.0%) or a respiratory tract infection (32/76, 42.1% and 21/76, 27.6%), while the lowest rates were documented in patients with intra-abdominal (5/38, 13.2% and 2/38, 5.3%) or urinary tract infections (6/40, 15.0% and 3/40, 7.5%). On bivariate analysis, additional variables associated with higher clinical failure included (Supplementary Appendix 2): CrCl ≤ 30 mL/min. or on hemodialysis, prior hospitalization within 90 days, ICU at infection onset, and SOFA score. Pursuit of source control, active antibiotic therapy within 48 hours of infection onset and CZA initiation within 48 hours of infection onset were associated with lower clinical failure. The use of CZA combination therapy did not impact overall clinical failure in the overall patient population or among high risk subgroups including those with primary bacteremia, a respiratory tract source, or ICU residence at Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 infection onset. Similarly, in patients with CRE or Pseudomonas spp. infections, combination therapy was not associated with lower clinical failure or lower 30-day mortality. Among eleven patients who received an inappropriate CZA dose reduction, five (45.5%) experience clinical failure and three (27.3%) died by day 30. The final multivariable logistic regression model for clinical failure is shown in Table 5. Primary bacteremia or respiratory tract infection and SOFA score were independently associated with higher clinical failure while CZA within 48 hours of infection onset was protective. Repeat CZA susceptibility testing was performed in 61 (30.0%) patients. The development of CZA resistance was not detected in any of these cultures. With regards to safety, 17 (8.4%) patients experienced a potential drug related adverse effect. Ten patients developed AKI while receiving CZA; nine of these patients were receiving concomitant nephrotoxic agents around the time of the event. In particular, five (25%) patients who received CZA combination therapy with an aminoglycoside or a polymyxin experienced AKI compared to 5 (3.2%) who did not receive either of these antibiotic classes with CZA (p < 0.001). Three patients developed C. difficile-associated diarrhea (two of whom received CZA combination therapy). Two patients had a rash and one patient each experienced possible drug-related neutropenia and GI intolerance. Discussion Antimicrobial resistance in gram-negative pathogens has now reached a critical point and 1, 2 many infections are no longer easily treated with carbapenems, the previous drugs of choice. Fortunately, a number of novel antibiotics targeted to one or more resistant determinants have 7, 22-24 recently been added to our armamentarium and others are in the pipeline. The introduction of these new agents, together with advances in rapid diagnostic techniques and progress in our understanding of pharmacokinetic/pharmacodynamic antibiotic optimization, have changed the landscape of treatment of MDR infections. Yet as our struggles with antimicrobial resistance will Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 continue despite the availability of new antibiotics, it is critically important that we learn how to best incorporate new agents into clinical practice. Real-world studies can provide valuable insights into the clinical role of new antibiotics. Therefore we conducted this study to evaluate the epidemiology and outcomes of patients treated with CZA from across the US for a range of MDR gram-negative pathogens. By some measures, CZA treatment appeared to be both effective and safe. Our primary outcome, composite clinical failure, occurred in 29.1% of patients and 30-day all-cause mortality was 17.2%. These results are particularly encouraging considering that our cohort was comprised of patients with high index illness severity and a variety of complex medical conditions. More than half of patients were residents of the ICU at infection onset, the median APACHE II score was 19 and greater than 40% had a Charlson Comorbidity score greater than four. CZA was also well tolerated. AKI occurred in 5.6% of patients not receiving renal replacement therapy at CZA initiation and the vast majority of these patients were receiving concomitant nephrotoxins. Furthermore, despite extensive prior antibiotic exposure and frequent use of CZA combination therapy, overall C. difficile- associated diarrhea rates were relatively low (1.5%). However, on a more sobering note, we observed considerable variation in outcomes by infection source with primary bacteremia and pneumonia portending particularly poor prognoses. Patients with severe renal impairment and those on chronic hemodialysis also did worse. These patterns have been observed by other investigators as well and serve as a reminder that in vitro antibiotic activity is not the only determinant of clinical outcomes in patients with MDR bacterial 10, 11, 13, 14, 16 infections. Interestingly, we found that CRE infections accounted for slightly more than half of infections treated with CZA in our cohort. Prior observational studies have focused primarily on CZA 10-16 for CRE infections. MDR Pseudomonas spp. was also a common indication for CZA in our cohort (n=63). To the best of our knowledge, this is the largest study of patients treated with CZA for Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas spp. infections reported to date. Patient characteristics and outcomes were remarkably similar when stratified by infecting pathogen, with the exception of infection source; a respiratory source of infection was more common in patients with Pseudomonas spp. infections. Among the P. aeruginosa isolates tested, CZA susceptibility was high (92.6%) and very similar to that of ceftolozane-tazobactam (85.2%). A great deal of regional variation has been observed with 25, 26 regards to the comparative activity of these antibiotics against MDR P. aeruginosa. Humphries et al. recently evaluated the comparative activity of ceftolozane-tazobactam and CZA against a collection of beta-lactam resistant P. aeruginosa isolates recovered from patients treated in Los Angeles, California. While both agents demonstrated good activity, susceptibility rates were lower than observed in our study and ceftolozane-tazobactam susceptibility rates were higher than CZA (72.5% and 61.8%, respectively). None of the centers that contributed cases to this study were located in California or the neighboring states, which may explain the differing results and underscores the importance of considering local resistance patterns to inform decisions at both the health system formulary level and for individual patients. It is also important to point out that our CZA susceptibility rates may be overestimates since we only included patients who received CZA for ≥ 72 hours (i.e. CZA may have not been started or stopped before 72 hours if resistance was detected). Combination therapy was considered standard for the treatment of CRE infections in the 2, 27 pre-CZA era. The marginal benefits of this approach however were often mitigated by overlapping toxicities. The use of CZA combination therapy was also common in our cohort with one in three patients receiving a second gram-negative targeted agent, most often an aminoglycoside or a polymyxin. Combination therapy was not associated with improved clinical outcomes however in the overall cohort nor in subgroups of higher risk patients. This finding is 10, 11, 13, 14 consistent with a number of recent CZA observational studies. AKI was significantly higher in patients who received a concomitant aminoglycoside or polymyxin. Although we cannot exclude confounding by indication, the consistent lack of benefit seen across studies and the potential for Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 harm demonstrated in the present study does call into question the utility of continuing this practice. We found that early in vitro active antibiotic therapy and in particular, early use of CZA (within 48 hours of infection onset), was associated with improved clinical outcomes. A number of studies have shown that treatment of serious infections is time sensitive with negative 28-31 consequences for delays in appropriate therapy. This underscores the important role of rapid diagnostic testing for early pathogen identification and susceptibility testing. New agents are often introduced before validated susceptibility testing methods are available and this may limit the benefit derived from their use. Nearly all patients enrolled in this study received an infectious disease consult at a median of 28 hours of infection onset. This was likely very important in ensuring the appropriate and optimal use of CZA. Rates of recurrence in our study were low (5.6%) and development of CZA on therapy resistance was not detected. These results compare favorably with one of the earliest CZA observational studies by Shields et al. These investigators evaluated 37 patients treated with CZA for CRE infections and found a 30-day recurrence rate of 16.7% including three patients with reinfection by a strain that had developed CZA resistance. Differences in patient and infection characteristics as well as study procedures may account for these discrepancies: 1) the study by Shields et al. included a larger proportions of patients with bacteremia and pneumonia which are characterized by high bacterial burdens; 2) we included patients with infections caused by a variety of pathogens vs. only CRE infections in the Shields, et al study; and 3) repeat susceptibility testing was performed in less than one-third of our patients (30.0%). This study has several important limitations including its retrospective, observational design. Additionally, although this represents one of the largest studies to date evaluating the use of CZA for MDR infections, the sample size was still relatively small, limiting our ability to conduct meaningful subgroup analyses. The use of rapid diagnostics varied across centers and CZA susceptibility testing Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 was performed on a relatively small proportion of isolates. We also did not have data regarding the mechanisms responsible for resistance. However, this is unfortunately reflective of real-world practice where, as noted previously, validated susceptibility testing methods often lag antibiotic approvals. Finally, the interpretation of CZA effectiveness and safety is limited by the lack of a control group. Comparative outcomes research of newer antibiotics is desperately needed. Indeed one may reasonably argue that there is no longer equipoise with regards to the comparative safety 12, 15, 32, 33 and efficacy of older more toxic regimens and newly approved CRE-active agents. Clinicians and patients would be better served if regulatory bodies would revise their guidance to the industry to stipulate that agents in late stage development targeted to MDR pathogens be compared to the new standard. In conclusion, our study adds to the growing body of literature describing CZA treatment patterns and outcomes for MDR infections. Our study shows that when patients are managed by infectious diseases physicians, CZA can be an effective therapy for MDR Pseudomonas as well as CRE infections. We provide additional data that should prompt clinicians to reassess the anticipated benefits and risks of combination therapy in the era of novel gram-negative agents. Our study also highlights the need for continued advances to improve outcomes in vulnerable patient groups including those with MDR gram-negative bacteremia or pneumonia and patients with severe renal impairment. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Acknowledgements This study has been presented, in part, at ID Week October 3 -7, 2018 San Francisco, CA (abstract 2379), ASM Microbe June 20 - 24, 2019, San Francisco, CA (abstract CIV-142) and ID Week October 1 – 6, 2019, Washington, DC (abstract 2254). Funding This study was funded by an investigator initiated grant from Allergan. Disclosures MJR: Research support, consultant or speaker for Allergan, Melinta, Merck, Motif, Nabriva, Paratek, Tetraphase and Shionogi KCC: Ad hoc board for Melinta Therapeutics JRR: Consulting agreements or is on the speakers bureau with Allergan, Merck, Shinogi, Tetraphase, Melinta, Paratek SLD: Consultant for Allergan, Sperow and Tetraphase. SJE: Employee of T2 Biosystems Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 All other authors have nothing to disclose References 1. Munita JM, Aitken SL, Miller WR et al. Multicenter Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa. Clin Infect Dis 2017; 65: 158-61. 2. Doi Y, Bonomo RA, Hooper DC et al. Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group. Clin Infect Dis 2017; 64: S30-S5. 3. Munoz-Price LS, Poirel L, Bonomo RA et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013; 13: 785-96. 4. Benattar YD, Omar M, Zusman O et al. The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study. Clin Infect Dis 2016; 63: 1605-12. 5. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999; 43: 1003-12. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 6. Panidis D, Markantonis SL, Boutzouka E et al. Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Chest 2005; 128: 545-52. 7. Zasowski EJ, Rybak JM, Rybak MJ. The beta-Lactams Strike Back: Ceftazidime- Avibactam. Pharmacotherapy 2015; 35: 755-70. 8. Karlowsky JA, Biedenbach DJ, Kazmierczak KM et al. Activity of Ceftazidime- Avibactam against Extended-Spectrum- and AmpC beta-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014. Antimicrob Agents Chemother 2016; 60: 2849-57. 9. Nichols WW, de Jonge BL, Kazmierczak KM et al. In Vitro Susceptibility of Global Surveillance Isolates of Pseudomonas aeruginosa to Ceftazidime-Avibactam (INFORM 2012 to 2014). Antimicrob Agents Chemother 2016; 60: 4743-9. 10. Caston JJ, Lacort-Peralta I, Martin-Davila P et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis 2017; 59: 118-23. 11. King M, Heil E, Kuriakose S et al. Multicenter Study of Outcomes with Ceftazidime- Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2017; 61. 12. Shields RK, Nguyen MH, Chen L et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother 2017; 61. 13. Shields RK, Potoski BA, Haidar G et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem- Resistant Enterobacteriaceae Infections. Clin Infect Dis 2016; 63: 1615-8. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 14. Temkin E, Torre-Cisneros J, Beovic B et al. Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms. Antimicrob Agents Chemother 2017; 61. 15. van Duin D, Lok JJ, Earley M et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis 2018; 66: 163-71. 16. Shields RK, Nguyen MH, Chen L et al. Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2018; 62. 17. Harris PA, Taylor R, Thielke R et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377-81. 18. Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-83. 19. Vincent JL, Moreno R, Takala J et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707-10. 20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41. 21. Evans SR HE, Doernberg S, Gouskova NA, Patillo S, Corey R, Boucher H, Fowler VG, Cosgrove SE, Chambers HF. Using endpoints to analyze patients rather than patients to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 analyze endpoints: a pre-trial substudy to develop a global outcome for clinical trials Society for Clinical Trials 37th Annual Meeting. Montreal, Quebec, Canada. 22. Abdul-Mutakabbir JC, Kebriaei R, Jorgensen SCJ et al. Teaching an Old Class New Tricks: A Novel Semi-Synthetic Aminoglycoside, Plazomicin. Infect Dis Ther 2019; 8: 155- 23. Heaney M, Mahoney MV, Gallagher JC. Eravacycline: The Tetracyclines Strike Back. Ann Pharmacother 2019: 1060028019850173. 24. Jorgensen SCJ, Rybak MJ. Meropenem and Vaborbactam: Stepping up the Battle against Carbapenem-resistant Enterobacteriaceae. Pharmacotherapy 2018; 38: 444-61. 25. Buehrle DJ, Shields RK, Chen L et al. Evaluation of the In Vitro Activity of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Meropenem-Resistant Pseudomonas aeruginosa Isolates. Antimicrob Agents Chemother 2016; 60: 3227-31. 26. Humphries RM, Hindler JA, Wong-Beringer A et al. Activity of Ceftolozane- Tazobactam and Ceftazidime-Avibactam against Beta-Lactam-Resistant Pseudomonas aeruginosa Isolates. Antimicrob Agents Chemother 2017; 61. 27. Alexander EL, Loutit J, Tumbarello M et al. Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials. Open Forum Infect Dis 2017; 4: ofx063. 28. Bonine NG, Berger A, Altincatal A et al. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status From Serious Gram-negative Bacterial Infections. Am J Med Sci 2019; 357: 103-10. 29. Seymour CW, Gesten F, Prescott HC et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med 2017; 376: 2235-44. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 30. Lodise TP, Jr., Patel N, Kwa A et al. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother 2007; 51: 3510-5. 31. Raman G, Avendano E, Berger S et al. Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis. BMC Infect Dis 2015; 15: 395. 32. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem- Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther 2018; 7: 439-55. 33. McKinnell JA, Dwyer JP, Talbot GH et al. Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae. N Engl J Med 2019; 380: 791-3. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 1: Demographic and clinical characteristics a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N= 117 N=63 Age, years 62 (49, 72) 63 (52, 73) 62 (43, 74) Age ≥ 65 years 90 (44.3) 53 (45.3) 28 (44.4) Male gender 39 (61.9) 63 (53.8) 39 (61.9) Race African American 93 (45.8) 57 (48.7) 30 (47.6) Caucasian 79 (38.9) 41 (35.0) 21 (33.3) Latino 8 (3.9) 6 (5.1) 3 (4.8) Other 22 (10.8) 13 (11.1) 9 (14.3) BMI 27 (22, 35) 27 (22, 34) 25 (21, 35) Obese (BMI ≥ 30 kg/m ) 77 (37.9) 40 (34.2) 23 (36.5) Estimated CrCl (mL/min) 65 (34, 105) 60 (29, 101) CrCl ≤ 30 mL/min 40 (19.7) 25 (21.4) 13 (20.6) CrCl 31-50 mL/min 28 (13.8) 14 (12.0) 10 (15.9) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 CrCl 51-90 mL/min 50 (24.6) 27 (23.1) 15 (23.8) CrCl 91 – 130 mL/min 28 (13.8) 18 (15.4) 7 (11.1) CrCl > 130 mL/min 27 (13.3) 13 (11.1) 11 (17.5) Hemodialysis 30 (14.8) 20 (17.1) 7 (11.1) Residence prior to admission Community 101 (49.8) 59 (50.4) 25 (39.7) SNF/LTAC 65 (32.0) 38 (32.5) 23 (11.3) Transferred from outside 28 (13.8) 14 (12.0) 11 (5.4) hospital Other 9 (4.4) 6 (3.0) 4 (2.0) Comorbid conditions Diabetes 85 (41.9) 46 (39.3) 33 (52.4) Heart Failure 37 (18.2) 20 (17.1) 12 (19.0) Chronic kidney disease 65 (32.0) 40 (34.2) 19 (30.2) Chronic lung disease 74 (36.5) 40 (34.2) 29 (46.0) Malignancy 27 (13.3) 19 (16.2) 6 (9.5) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Liver disease 21 (10.3) 15 (12.8) 2 (3.2) Charlson Comorbidity score 4 (2, 6) 4 (2, 7) 4 (2, 6) Charlson Comorbidity score > 4 85 (41.9) 51 (43.6) 25 (39.7) Immunocompromised 22 (10.8) 16 (13.7) 4 (6.3) MDRO infection or colonization 97 (47.8) 56 (47.9) 34 (54.0) within 1 year Recent antibiotic exposure 157 (77.3) 96 (82.1) 51 (81.0) (≥ 24 hours within 90 days) Recent hospitalization 151 (74.4) 94 (80.3) 46 (73.0) (≥ 48 hours within 90 days) Recent surgery 38 (18.7) 23 (19.7) 10 (15.9) (within 30 days) ICU at index culture 102 (50.2) 62 (53.0) 35 (55.6) SOFA score 5 (2, 8) 5 (2, 8) 5 (2, 8) a. All values represent number (%) or median (interquartile range) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 b. Estimated by using the Cockroft Gault equation ; creatinine measured within 24 hours of first dose ceftazidime-avibactam; BMI: body mass index; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; ICU: intensive care unit; LTAC: long-term acute care hospital; MDRO: multidrug-resistant organism; SOFA: Sequential Organ Failure Assessment; SNF: skilled nursing facility Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 2: Infection characteristics a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Hospital-acquired infection 117 (57.6) 71 (60.7) 38 (60.3) Hours from admission to culture 3 (2, 16) 6 (2, 17) 73 (2, 13) collection Infection Source Primary bacteremia 10 (4.9) 7 (6.0) 1 (1.6) Respiratory 76 (37.4) 39 (33.3) 38 (60.3) Intra-abdominal 38 (18.7) 26 (22.2) 3 (4.8) Skin and soft tissue 18 (8.9) 8 (8.8) 6 (9.5) Osteoarticular 14 (6.9) 7 (6.0) 6 (9.5) Urine 40 (19.7) 24 (20.4) 7 (11.1) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Prosthetic device 2 (1.0) 2 (1.7) 0 Intravenous catheter 4 (2.0) 3 (2.6) 2 (3.2) Other 1 (0.5) 1 (0.9) 0 Positive blood cultures 22 (10.8) 10 (8.5) 3 (4.8) Organism Enterobacteriacea 159 (78.3) 117 (100) Klebsiella pneumoniae 89 (43.8) 74 (63.2) K. oxytoca 8 (3.9) 5 (4.3) Escherichia coli 23 (11.3) 17 (14.5) Enterobacter spp. 29 (14.3) 15 (12.8) Proteus mirabilis 8 (3.9) 1 (0.9) Citrobacter spp. 9 (4.4) 5 (4.3) Serratia marcescens 6 (3.0) 4 (3.4) Providentia stuarti 4 (2.0) 0 Morganella morganii 4 (2.0) 0 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas spp. 63 (31.0) Acinetobacter spp. 12 (5.9) Stenotrophomonas maltophilia 5 (2.5) Gram-positive 30 (14.8) Polymicrobial infection 48 (23.6) 30 (25.6) 17 (27.0) K. pneumoniae CZA MIC (mg/L) MIC 1 1 MIC 2 4 N=51 N=43 P. aeruginosa CZA MIC (mg/L) MIC MIC 2 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 N=19 a. All values represent number (%) or median (interquartile range) b. Perinephric abscess c. Eleven of 12 patients had polymicrobial infections and received additional other antibiotics targeting Acinetobacter spp. The remaining patient had monomicrobial Acinetobacter UTI. They received CZA (surprisingly MIC 8 mg/ml) plus minocycline. The rationale for using CZA was not explicitly stated. d. All patients had polymicrobial infections and received additional other antibiotics targeting S. maltophilia CRE: carbapenem-resistant Enterobacteriaceae; CZA: ceftazidime-avibactam; MIC: minimum inhibitory concentration Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 3: Treatment information a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Infectious disease consult 199 (98.0) 117 (100) 59 (93.7) b c Time to infectious disease 28 (4, 63) 29 (9, 65) 24 (0, 86) consult (hours) Surgical consult 58 (28.6) 32 (27.4) 17 (27.0) Source control pursued 54 (26.6) 29 (24.8) 19 (30.2) Active antibiotic(s) before CZA 54 (26.6) 27 (23.1) 12 (19.0) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Time to active antibiotic(s) 55 (7, 102) 69 (26, 103) 72 (12, 123) (hours) Active antibiotic(s) within 48 91 (44.8) 39 (33.3) 24 (38.1) hours Time to CZA (hours) 85 (42, 146) 93 (52, 145) 94 (34, 170) CZA within 48 hours 59 (29.1) 25 (21.4) 17 (27.0) Renal CZA dose adjustment 92 (45.3) 54 (46.2) 28 (44.4) CZA combination therapy 68 (33.5) 45 (38.5) 20 (31.7) Aminoglycoside 21 (10.3) 13 (11.1) 8 (12.7) Colistin / polymyxin B 17 (8.4) 10 (8.5) 5 (7.9) Fluoroquinolone 10 (4.9) 8 (6.8) 2 (3.2) Tigecycline 16 (7.9) 10 (8.5) 3 (4.8) Minocycline 2 (1.0) 1 (0.9) 0 Aztreonam 3 (1.5) 1 (0.9) 2 (3.2) Inhaled antibiotic therapy in 19/76 (25.0) 7/39 (7.9) 14/38 (36.8) patients with a respiratory tract Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 infection CZA duration (days) 9 (6, 16) 13 (6, 18) 9 (5, 14) a. All values represent number (%) or median (interquartile range) b. N = 199 c. N = 59 d. Inhaled tobramycin or colistin CRE: carbapenem-resistant Enterobacteriaceae;; CZA: ceftazidime-avibactam Table 4: Outcomes a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Effectiveness Discharge disposition Home 57 (28.1) 31 (26.5) 16 (25.4) SNF/LTAC 90 (44.3) 53 (45.3) 32 (50.8) Inpatient rehabilitation 14 (6.9) 8 (6.8) 3 (4.8) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 facility Hospice 8 (3.9) 5 (4.3) 2 (3.2) In hospital mortality 34 (16.7) 20 (17.1) 10 (15.9) Discharge disposition among patients admitted from home Home 47 /101 (46.5) 25 / 59 (42.4) 11 / 25 (44.0) SNF/LTAC 29 /101 (28.7) 18 / 59 (30.5) 9 / 25 (36.0) Inpatient rehabilitation facility 10 /101 (9.9) 6 / 59 (10.2) 3/25 (12.0) Hospice In hospital mortality 2 /101 (2.0) 2/ 59 (3.4) 0 13 / 101 (12.9) 8 / 59 (13.6) 2/ 25 (8.0) Composite clinical failure 59 (29.1) 34 (29.1) 19 (30.2) 30-day mortality 35 (17.2) 19 (16.2) 11 (17.5) 30-day recurrence 12 (5.9) 7 (6.0) 4 (6.3) Worsen or failure to 32 (15.8) 18 (15.4) 12 (19.0) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 improve while on CZA Development of CZA resistance 0 0 0 (n=61) Safety Acute kidney injury 10/177 (5.6) 5/101 (5.0) 4/56 (7.1) Clostridioides difficile infection 3 (1.5) 3 (2.6) 0 Rash 2 (1.0) 0 2 (3.2) a. All values represent number (%) or median (interquartile range) b. Evaluated in patients with follow-up cultures c. Patients receiving hemodialysis excluded CRE: carbapenem-resistant Enterobacteriaceae; CZA: ceftazidime-avibactam Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 5: Multivariable logistic regression model for clinical failure Variable Adjusted odds ratio (95% CI) P value Primary bacteremia or respiratory tract 2.270 (1.115, 4.620) < 0.001 infection SOFA score 1.234 (1.118, 1.362) 0.0238 CZA within 48 hours of culture collection 0.409 (0.180, 0.930) 0.0329 a. Variable considered for model entry were: admission from an outside hospital, CrCl ≤ 30 mL/min or receipt of hemodialysis, previous hospitalization within 90 days, hospital-acquired infection, primary bacteremia or respiratory tract infection, pursuit of source control, early (≤ 48 hours) active antibiotic therapy, early (≤ 48 hours) CZA, APACHE II score, SOFA score, ICU at infection onset APACHE: Acute Physiological and Chronic Health Evaluation; CI: confidence interval; CrCl: creatinine clearance; CZA: ceftzidime-avibactam; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Supplementary Appendix 1 Carbapenem-resistant Klebsiella pneumoniae antibiogram Organism Percent susceptible Ceftazidime- Amikacin Gentamicin Colistin Tigecycine Meropenem avibactam CR-K. pneumoniae 96.0% 66.7% 65.7% 100.0% 64.4% 14.5% N=50 N=33 N=70 N=44 N=45 N=62 a. Clinical and Laboratory Standards Institute (CLSI) 2019 breakpoints used for all antibiotics except colistin for which the EUCAST breakpoint of 2 mg/mL was applied CR: carbapenem-resistant Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas aeruginosa antibiogram Organism Percent susceptible Ceftazidime- Ceftolozane- Amikacin Tobramycin Ceftazidime Piperacillin- Meropenem avibactam tazobactam tazobactam Pseudomonas 92.6% 85.2% 94.0% 78.0% 52.5% 28.0% 22.5% aeruginosa N=27 N=27 N=50 N=50 N=40 N=50 N=49 a. Clinical and Laboratory Standards Institute (CLSI) 2019 breakpoints used for all antibiotics Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Supplementary Appendix 2 Univariate analyses for clinical failure a a Clinical success Clinical failure Odds ratio (95% CI) P value N=144 N=59 Age, years 0.989 (0.972, 1.008) 0.251 Age ≥ 65 years 69 (47.9) 21 (35.6) 0.601 (0.321, 1.122) 0.109 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Male gender 80 (55.6) 31 (52.5) 0.886 (0.482, 1.626) 0.695 African American 61 (42.4) 32 (54.2) 1.613 (0.877, 2.967) 0.123 BMI 1.025 (0.994, 1.057) 0.118 Obese (BMI ≥ 30 kg/m ) 51 (35.4) 26 (44.1) 1.437 (0.775, 2.663) 0.249 Estimated CrCl (mL/min) CrCl ≤ 30 mL/min 26 (18.1) 14 (23.7) 1.615 (0.552, 4.729) 0.382 CrCl 31-50 mL/min 24 (16.7) 4 (6.8) 0.500 (0.128, 1.950) 0.318 CrCl 51-90 mL/min 36 (25.0) 14 (23.7) 1.167 (0.406, 3.350) 0.775 CrCl 91 – 130 mL/min 21 (14.6) 7 (11.9) Reference --- CrCl > 130 mL/min 20 (13.9) 7 (11.9) 1.050 (0.312, 3.533) 0.937 Hemodialysis 17 (11.8) 13 (22.0) 2.294 (0.749, 7.027) 0.146 CrCl ≤ 30 mL/min or hemodialysis 43 (29.9) 27 (45.8) 1.982 (1.062, 3.700) 0.030 Residence prior to admission Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Community 74 (51.4) 27 (45.8) Reference --- SNF/LTAC 47 (32.6) 18 (30.5) 1.050 (0.521, 2.113) 0.892 Transferred from 16 (11.1) 12 (20.3) 2.056 (0.862, 4.899) 0.104 outside hospital Other 7 (4.9) 2 (3.4) 0.783 (0.153, 4.005) 0.769 Comorbid conditions Diabetes 60 (41.7) 25 (42.4) 1.029 (0.557, 1.901) 0.926 Heart Failure 25 (17.4) 12 (20.3) 1.215 (0.565, 2.616 0.618 Chronic kidney 41 (28.5) 24 (40.7) 1.723 (0.915, 3.244) 0.091 disease Chronic lung disease Malignancy 15 (10.4) 6 (10.2) 0.974 (0.358, 2.645) 0.958 Liver disease 20 (13.9) 7 (11.9) 0.835 (0.333, 2.094) 0.700 Charlson Comorbidity score 1.051 (0.947, 1.168) 0.349 Charlson Comorbidity score > 57 (39.6) 28 (47.5) 1.379 (0.749, 2.538) 0.302 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Immunocompromised 13 (9.0) 9 (15.3) 1.814 (0.730, 4507) 0.195 MDRO infection or 70 (48.6) 27 (45.8) 0.892 (0.486, 1.638) 0.712 colonization within 1 year Recent antibiotic exposure 108 (75.0) 49 (83.1) 1.633 (0.750, 3.555) 0.213 (≥ 24 h within 90 days) Recent hospitalization (≥ 48 101 (70.1) 50 (84.7) 2.365 (1.069, 5.234) 0.030 hours within 90 days) Recent surgery (within 30 28 (19.4) 10 (16.9) 0.845 (0.382, 1.873) 0.679 days) ICU at index culture 62 (43.1) 40 (67.8) 2.784 (1.471, 5.270) 0.001 SOFA score 1.264 (1.155, 1.385) < 0.001 Hospital-acquired infection 74 (51.4) 43 (72.9) 2.542 (1.313, 4.921) 0.005 Infection Source Primary bacteremia 3 (2.1) 7 (11.9) Respiratory 44 (30.6) 32 (54.2) Intra-abdominal 33 (22.9) 5 (8.5) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Skin and soft tissue 13 (9.0) 5 (8.5) Osteoarticular 12 (8.3) 2 (3.4) Urine 34 (23.6) 6 (10.2) Prosthetic device 2 (1.4) 0 Intravenous catheter 2 (1.4) 2 (3.4) Other 1 (0.7) 0 Primary bacteremia or 47 (32.6) 39 (66.1) 4.024 (2.118, 7.646) < 0.001 respiratory tract infection Positive blood cultures 13 (9.0) 9 (15.3) 1.814 (0.730, 4.507) 0.195 Secondary bacteremia 10 (6.9) 2 (3.4) 0.470 (0.100, 2.214) 0.515 CRE 83 (57.6) 34 (57.6) 1.000 (0.541, 1.845) 0.999 Pseudomonas spp. 44 (30.6) 19 (32.2) 1.080 (0.563, 2.070) 0.818 Polymicrobial infection 34 (23.6) 14 (23.7) 1.007 (0.494, 2.052) 0.986 Treatment information Infectious disease consult 140 (97.2) 59 (100.0) 1.421 (1.299, 1.556) 0.325 Time to infectious diseases 1.000 (0.999, 1.001) 0.674 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 consult Infectious diseases consult ≤ 96 (68.6) 40 (67.8) 0.965 (0.503, 1.853) 0.915 48 hours after culture collection Surgical consult 42 (29.2) 16 (27.1) 0.904 (0.459, 1.779) 0.769 Source control pursued 44 (30.6) 10 (16.9) 0.464 (0.215, 0.999) 0.046 Active antibiotic(s) before 38 (26.4) 16 (27.1) 1.038 (0.524, 2.005) 0.915 CZA Time to active antibiotic(s) 1.000 (0.998, 1.002) 0.682 (hours) Active antibiotic therapy ≤ 48 71 (49.3) 20 (33.9) 0.527 (0.281, 0.990) 0.045 hours after culture collection Time to CZA (h) 1.001 (0.999, 1.002) 0.603 CZA within 48 hour 48 (33.3) 11 (18.6) 0.458 (2.18, 0.962) 0.036 CZA within 72 hours 64 (44.4) 23 (39.0) 0.799 (0.431, 1.481) 0.475 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 CZA within 96 hours 83 (57.6) 29 (49.2) 0.710 (0.387, 1.305) 0.270 CZA within 120 hours 100 (69.4) 36 (61.0) 0.689 (0.366, 1.296) 0.246 Combination IV antibiotic 44 (30.6) 24 (40.7) 1.558 (0.831, 2.923) 0.165 therapy with CZA Inhaled antibiotic therapy 10 (6.9) 11 (18.6) 3.071 (1.227, 7.687) 0.013 CZA renal dose adjustment 61 (42.4) 31 (52.5) 1.506 (0.820, 2.769) 0.186 a. All values represent number (%) or median (interquartile range) b. N = 199 BMI: body mass index; CI: confidence interval; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; CZA: ceftazidime-avibactam; ICU: intensive care unit; LTAC: long-term acute care hospital; MDRO: multidrug-resistant organism; SOFA: Sequential Organ Failure Assessment; SNF: skilled nursing facility Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Loading next page...
 
/lp/oxford-university-press/real-world-experience-with-ceftazidime-avibactam-for-multidrug-WGazisJTJf

References (41)

Publisher
Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
eISSN
2328-8957
DOI
10.1093/ofid/ofz522
Publisher site
See Article on Publisher Site

Abstract

Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections Sarah C.J. JORGENSEN 1,2 Trang D. TRINH 1,3 Evan J. ZASOWSKI Abdalhamid M. LAGNF Sahil BHATIA Sarah M. MELVIN Molly E. STEED Samuel P. SIMON 6,7 Sandra J. ESTRADA 1,8 Taylor MORRISETTE Kimberly C. CLAEYS Joshua R. ROSENBERG 1,10 Susan L. DAVIS © The Author(s) 2019. 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 © The Author(s) 2019. 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 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 1,11,12 Michael J. RYBAK 1. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA 2. Medication Outcomes Center, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA 3. Department of Clinical Sciences, College of Pharmacy, Touro University California, Vallejo, CA 4. Department of Pharmacy Practice, School of Pharmacy, University of Kansas, Kansas City, KS 5. Brooklyn Hospital, Brooklyn, NY 6. Department of Pharmacy, Lee Health, Fort Myers, FL 7. T2 Biosystems Inc, Lexington, MA 8. Department of Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States 9. Department of Pharmacy Practice, School of Pharmacy, University of Maryland, Baltimore, MD 10. Department of Pharmacy, Henry Ford Hospital, Detroit, MI 11. Department of Medicine, Wayne State University, Detroit, MI 12. Department of Pharmacy, Detroit Medical Center, Detroit, MI Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Corresponding Author Michael J. Rybak Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University 259 Mack Ave., Detroit, MI, USA, 48201 Phone: 313-577-4376 Fax: 313-577-9310 Email m.rybak@wayne.edu Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Abstract Objective To describe the clinical characteristics, microbiology and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant gram-negative (MDR-GN) infections. Methods Multicenter, retrospective cohort study at six medical centers in the U.S. between 2015 and 2019. Adult patients who received CZA (≥72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure and/or failure to resolve or improve signs or symptoms of infection on CZA. Results In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp. were isolated from 117(57.6%) and 63(31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%) and intra-abdominal (18.7%). Blood cultures were positive in 22(10.8%) patients. Clinical failure, 30-day mortality and 30-day recurrence occurred in 59(29.1%), 35(17.2%) and 12(5.9%) patients, respectively. On therapy CZA resistance developed in one of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (aOR 2.270, 95% CI 1.115-4.620 and aOR 1.234, 95% CI 1.118-1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR 0.409 95% CI 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (ten acute kidney injury, three Clostridioides difficile infection, two rash and one each gastrointestinal intolerance and neutropenia) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Conclusions CZA is being used to treat a range of MDR-GN infections including Pseudomonas spp. as well as CRE. Keywords Ceftazidime-avibactam, carbapenem-resistant Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Introduction Multidrug-resistant (MDR) gram-negative bacteria are a pressing infectious disease 1, 2 challenge. Carbapenems have served as the antibiotics of choice for infections caused by these pathogens for decades. However, the emergence and spread of carbapenemases threatens their utility as our last line of defense against MDR bacteria. The predominant carbapenemase in the United States is Klebsiella pneumoniae carbapenemase (KPC), an Ambler class A enzyme that hydrolyses nearly all currently available beta‐lactams. Bacteria that harbor blaKPC often carry other genes that encode resistance to a wide array of other antibiotic classes, posing a serious treatment 2, 3 challenge. Until recently, the only remaining antibiotics with preserved in vitro activity against 4-6 MDR strains were limited by unfavorable pharmacokinetic properties and/or toxicity. The high morbidity and mortality associated with infections caused by MDR gram-negative bacteria is partly due to the paucity of safe and effective treatment options, attesting to the need for continued antibiotic development. Ceftazidime-avibactam (CZA) is a combination antimicrobial consisting of an established antipseudomonal cephalosporin and a novel non-beta-lactam (diazabicyclooctane) beta-lactamase inhibitor. Avibactam protects ceftazidime from hydrolysis by Ambler class A and some class D carbapenemases. In surveillance studies, CZA has demonstrated in vitro activity against 8, 9 carbapenem-resistant Enterobatceriaceae (CRE) and MDR Pseudomonas aeruginosa. Real-world Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 experience with CZA for the treatment of CRE infections is slowly accumulating but data on its use 10-16 for other MDR gram-negative pathogens including P. aeruginosa remains limited. We sought to add to this data and describe the clinical characteristics, microbiology and outcomes of patients treated with CZA for a range of MDR gram-negative bacterial pathogens. Methods Study design and population This was a multicenter, retrospective, observational cohort study conducted at six geographically diverse academic medical centers in the U.S. between 2015 and 2019. Inclusion criteria were: 1) age ≥ 18 years and 2) receipt of ≥ 72 hours of CZA. For each patient, only the initial CZA treatment course during the study period was included. Ethics Approval was obtained from each participating center’s Institutional Review Board with a waiver for informed consent. Data collection and study definitions Pharmacy records were screened for all patients who received at least one dose of CZA during the study period. For eligible patients, demographic, clinical, microbiological and treatment data were extracted from the electronic medical record and entered into a secure data collection form. Bacterial identification and antibiotic susceptibilities were performed at each center according to standard procedures. CZA susceptibility was determined using disk diffusion or gradient strips, where available. CRE was defined by current U.S. Centers for Disease Control and Prevention (CDC) criteria. Infection onset was considered to be when the index culture was collected. Sources of infection were based on the treating physician’s notes and available clinical, microbiological and diagnostic data. The infection was classified as hospital-acquired if the index culture was obtained Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 greater than 48 hours after admission. Comorbidity burden was quantified using the Charlson 18 19 Comorbidity score. Severity of illness at infection onset was quantified using the SOFA score. CZA was administered as a standard dose of 2.5g IV every eight hours with dose adjustments based on estimate creatinine clearance (Cockroft Gault equation) according to the manufacturer’s recommendations. For the purposes of this study, CZA combination therapy was defined as the receipt of a concomitant gram-negative targeted antibiotic for ≥ 48 hours with CZA. Receipt of metronidazole was described separately. Microbiological failure was defined as infection recurrence with the same organism as isolated from the index culture after seven days of CZA therapy to the end of follow-up plus signs and symptoms of infection. Data were collected for up to 30 days following discharge (i.e. from health system outpatient clinics, rehabilitation centers, emergency departments and hospital re-admissions where available). Clinical failure was defined as a composite of all-cause 30-day mortality, microbiological failure and/or failure to resolve or improve signs and symptoms of infections during CZA therapy. Acute kidney injury (AKI) was evaluated in patients not receiving hemodialysis at the time of CZA initiation and was defined as a serum creatinine increase of ≥ 0.5 mg/dL or 50% from baseline on two consecutive measurements while on CZA and up to 72 hours following the last dose. Statistical analysis: Baseline characteristics of the overall cohort and in the CRE and Pseudomonas spp. subgroups were evaluated using descriptive statistics; discrete data were reported as counts and percentages and continuous data were reported as medians and interquartile ranges (IQR). Multivariable logistic regression analysis was performed to identify independent predictors of clinical failure. Since baseline characteristics, management and outcomes were similar in the overall cohort and the CRE and Pseudomonas spp. subgroups, this analysis was conducted using the overall cohort. Clinically relevant variables were selected for model entry based on bivariate comparisons (P < 0.2) and biological plausibility. Some variables were collapsed into single composite variables when the Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 number of patients in subgroups was too small to allow for meaningful analysis. The selected model was simplified based on the Akaike Information Criterion (AIC) in backward fashion. Multicollinearity of candidate regression models was assessed via the variance inflation factor, with values less than three considered acceptable. Secondary outcomes of interest included individual components of the composite outcome, discharge disposition, emergence of CZA resistance during treatment and hospital length of stay. Safety outcomes included AKI, dermatological reactions, cytopenias, central nervous system disturbances, gastrointestinal intolerance, and Clostridioides difficile-associated diarrhea. All analyses were performed using SPSS Statistics version 24.0 (IBM corp., Armonk, NY) and SAS 9.4 Statistical Software (SAS Institute Inc., Cary, NC). A two-tailed P value less than 0.05 was considered statistically significant. Results: Patient characteristics In total, 203 patients met study inclusion criteria and were evaluated. A complete description of patient baseline demographic and clinical characteristics are displayed in Table 1. Overall, the study cohort had a median age of 62 (IQR 49, 72) years with a high burden of medical comorbidity (median Charlson Comorbidity score 4 IQR 2, 6). Nearly half (93, 45.8%) of patients resided in a skilled nursing facility prior to admission or were transferred from an outside hospital and the majority of patients had a recent (90 day) history of hospitalization or systemic antibiotic exposure (151, 74.4% and 157, 77.3%, respectively). Many patients had a high severity of illness at infection onset with 102 (50.2%) residing in the ICU and a median (IQR) SOFA score of 5 (2, 8). Baseline characteristic of patients with CRE or Pseudomonas spp. infections were similar (Table 1). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Infection characteristics The majority of infections (117, 57.6%) were hospital-acquired with the median (IQR) time from admission to infection onset of 3 (2, 16) days. The most common infection sources were respiratory tract (76, 37.4%), followed by urinary tract (40, 19.7%), intra-abdominal (38, 18.7%), skin and soft tissue (18, 8.9%) and osteoarticular (14, 6.9%) (Table 2). Blood cultures were positive in 22 (10.8%) patients. CRE was isolated from 117 (57.6%) of culture specimens. Most CRE were K. pneumoniae (74/117, 63.2%), followed by E. coli (17/117, 14.5%) and Enterobacter spp. (15/117, 12.8%). Among the 50 carbapenem-resistant K. pneumoniae isolates tested, 48 (96.0%) were susceptible to CZA. One resistant isolate (CZA MIC > 256 mg/L) harbored both NDM and OXA carbapenemases. The mechanism of resistance in the second isolate is currently unknown. CZA was used to treat 63 patients with Pseudomonas spp. infections. The majority of Pseudomonas spp. infections had a respiratory tract source (38, 60.3%). Among the P. aeruginosa isolates for which the CZA susceptibility testing was performed (n=27), 25 (92.6%) were susceptible. One isolate demonstrated intermediate CZA susceptibility (zone diameter 18 mm) and a second was CZA resistant (MIC > 256 mg/L, positive for NDM and OXA carbapenemases). Of 40 P.aeruginosa isolates tested, 21 (52.5%) were susceptible to ceftazidime itself. The most common reason for the use of CZA in these patients was co-infection with CRE (n = 11) and cefepime resistance or failure in hospitals that did not carry ceftazidime on the formulary (n = 6). K. pneumoniae and P. aeruginosa antibiograms are shown in Supplementary Appendix 1. Infection management A summary of infection management is shown in Table 3. Overall 199 (98.0%) and 58 (28.6%) patients received an infectious disease or surgical consult, respectively and source control (e.g. line removal, abscess drainage) was pursued in 54 (26.6%) patients. The median time from culture collection to CZA initiation was 85 (42, 146) hours. Approximately one in four (54, 26.6%) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 patients received in vitro active antibiotic therapy prior to CZA with an overall median time to active antibiotic therapy of 55 (7, 102) hours. The most commonly used active agents prior to CZA were aminoglycosides (18/54, 33.3%). The CZA dose was renally adjusted in 92 (45.3%) patients. Eleven of these patients did not require dose adjustment based estimated CrCl > 50 mL/min at the start of CZA. Combination IV antibiotic therapy was used 68 (33.5%) patients, most commonly with an aminoglycoside (21, 10.3%), colistin / polymyxin B (17, 8.4%) or tigecycline (16, 7.9%). Three of 38 patients (7.9%) with an intra-abdominal infection received concomitant metronidazole. Inhaled antibiotics (tobramycin or colistin) were used in 19 of 76 patients (25.0%) with a respiratory tract infection. The median duration of inpatient CZA was 9 (6, 16) days. Outcomes Patient outcomes are displayed in Table 4. As shown, outcomes were similar in patients with CRE and Pseudomonas spp. infections. Overall, composite clinical failure and 30-day mortality occurred in 59 (29.1%) and 35 (17.2%) patients, respectively. Among patients originally admitted from home (n = 101), 29 (28.7%) and 10 (9.9%) required new nursing home placement or inpatient rehabilitation following discharge, respectively. The highest rates of clinical failure and 30-day mortality were recorded in patients with primary bacteremia (7/10, 70.0% and 4/10, 40.0%) or a respiratory tract infection (32/76, 42.1% and 21/76, 27.6%), while the lowest rates were documented in patients with intra-abdominal (5/38, 13.2% and 2/38, 5.3%) or urinary tract infections (6/40, 15.0% and 3/40, 7.5%). On bivariate analysis, additional variables associated with higher clinical failure included (Supplementary Appendix 2): CrCl ≤ 30 mL/min. or on hemodialysis, prior hospitalization within 90 days, ICU at infection onset, and SOFA score. Pursuit of source control, active antibiotic therapy within 48 hours of infection onset and CZA initiation within 48 hours of infection onset were associated with lower clinical failure. The use of CZA combination therapy did not impact overall clinical failure in the overall patient population or among high risk subgroups including those with primary bacteremia, a respiratory tract source, or ICU residence at Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 infection onset. Similarly, in patients with CRE or Pseudomonas spp. infections, combination therapy was not associated with lower clinical failure or lower 30-day mortality. Among eleven patients who received an inappropriate CZA dose reduction, five (45.5%) experience clinical failure and three (27.3%) died by day 30. The final multivariable logistic regression model for clinical failure is shown in Table 5. Primary bacteremia or respiratory tract infection and SOFA score were independently associated with higher clinical failure while CZA within 48 hours of infection onset was protective. Repeat CZA susceptibility testing was performed in 61 (30.0%) patients. The development of CZA resistance was not detected in any of these cultures. With regards to safety, 17 (8.4%) patients experienced a potential drug related adverse effect. Ten patients developed AKI while receiving CZA; nine of these patients were receiving concomitant nephrotoxic agents around the time of the event. In particular, five (25%) patients who received CZA combination therapy with an aminoglycoside or a polymyxin experienced AKI compared to 5 (3.2%) who did not receive either of these antibiotic classes with CZA (p < 0.001). Three patients developed C. difficile-associated diarrhea (two of whom received CZA combination therapy). Two patients had a rash and one patient each experienced possible drug-related neutropenia and GI intolerance. Discussion Antimicrobial resistance in gram-negative pathogens has now reached a critical point and 1, 2 many infections are no longer easily treated with carbapenems, the previous drugs of choice. Fortunately, a number of novel antibiotics targeted to one or more resistant determinants have 7, 22-24 recently been added to our armamentarium and others are in the pipeline. The introduction of these new agents, together with advances in rapid diagnostic techniques and progress in our understanding of pharmacokinetic/pharmacodynamic antibiotic optimization, have changed the landscape of treatment of MDR infections. Yet as our struggles with antimicrobial resistance will Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 continue despite the availability of new antibiotics, it is critically important that we learn how to best incorporate new agents into clinical practice. Real-world studies can provide valuable insights into the clinical role of new antibiotics. Therefore we conducted this study to evaluate the epidemiology and outcomes of patients treated with CZA from across the US for a range of MDR gram-negative pathogens. By some measures, CZA treatment appeared to be both effective and safe. Our primary outcome, composite clinical failure, occurred in 29.1% of patients and 30-day all-cause mortality was 17.2%. These results are particularly encouraging considering that our cohort was comprised of patients with high index illness severity and a variety of complex medical conditions. More than half of patients were residents of the ICU at infection onset, the median APACHE II score was 19 and greater than 40% had a Charlson Comorbidity score greater than four. CZA was also well tolerated. AKI occurred in 5.6% of patients not receiving renal replacement therapy at CZA initiation and the vast majority of these patients were receiving concomitant nephrotoxins. Furthermore, despite extensive prior antibiotic exposure and frequent use of CZA combination therapy, overall C. difficile- associated diarrhea rates were relatively low (1.5%). However, on a more sobering note, we observed considerable variation in outcomes by infection source with primary bacteremia and pneumonia portending particularly poor prognoses. Patients with severe renal impairment and those on chronic hemodialysis also did worse. These patterns have been observed by other investigators as well and serve as a reminder that in vitro antibiotic activity is not the only determinant of clinical outcomes in patients with MDR bacterial 10, 11, 13, 14, 16 infections. Interestingly, we found that CRE infections accounted for slightly more than half of infections treated with CZA in our cohort. Prior observational studies have focused primarily on CZA 10-16 for CRE infections. MDR Pseudomonas spp. was also a common indication for CZA in our cohort (n=63). To the best of our knowledge, this is the largest study of patients treated with CZA for Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas spp. infections reported to date. Patient characteristics and outcomes were remarkably similar when stratified by infecting pathogen, with the exception of infection source; a respiratory source of infection was more common in patients with Pseudomonas spp. infections. Among the P. aeruginosa isolates tested, CZA susceptibility was high (92.6%) and very similar to that of ceftolozane-tazobactam (85.2%). A great deal of regional variation has been observed with 25, 26 regards to the comparative activity of these antibiotics against MDR P. aeruginosa. Humphries et al. recently evaluated the comparative activity of ceftolozane-tazobactam and CZA against a collection of beta-lactam resistant P. aeruginosa isolates recovered from patients treated in Los Angeles, California. While both agents demonstrated good activity, susceptibility rates were lower than observed in our study and ceftolozane-tazobactam susceptibility rates were higher than CZA (72.5% and 61.8%, respectively). None of the centers that contributed cases to this study were located in California or the neighboring states, which may explain the differing results and underscores the importance of considering local resistance patterns to inform decisions at both the health system formulary level and for individual patients. It is also important to point out that our CZA susceptibility rates may be overestimates since we only included patients who received CZA for ≥ 72 hours (i.e. CZA may have not been started or stopped before 72 hours if resistance was detected). Combination therapy was considered standard for the treatment of CRE infections in the 2, 27 pre-CZA era. The marginal benefits of this approach however were often mitigated by overlapping toxicities. The use of CZA combination therapy was also common in our cohort with one in three patients receiving a second gram-negative targeted agent, most often an aminoglycoside or a polymyxin. Combination therapy was not associated with improved clinical outcomes however in the overall cohort nor in subgroups of higher risk patients. This finding is 10, 11, 13, 14 consistent with a number of recent CZA observational studies. AKI was significantly higher in patients who received a concomitant aminoglycoside or polymyxin. Although we cannot exclude confounding by indication, the consistent lack of benefit seen across studies and the potential for Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 harm demonstrated in the present study does call into question the utility of continuing this practice. We found that early in vitro active antibiotic therapy and in particular, early use of CZA (within 48 hours of infection onset), was associated with improved clinical outcomes. A number of studies have shown that treatment of serious infections is time sensitive with negative 28-31 consequences for delays in appropriate therapy. This underscores the important role of rapid diagnostic testing for early pathogen identification and susceptibility testing. New agents are often introduced before validated susceptibility testing methods are available and this may limit the benefit derived from their use. Nearly all patients enrolled in this study received an infectious disease consult at a median of 28 hours of infection onset. This was likely very important in ensuring the appropriate and optimal use of CZA. Rates of recurrence in our study were low (5.6%) and development of CZA on therapy resistance was not detected. These results compare favorably with one of the earliest CZA observational studies by Shields et al. These investigators evaluated 37 patients treated with CZA for CRE infections and found a 30-day recurrence rate of 16.7% including three patients with reinfection by a strain that had developed CZA resistance. Differences in patient and infection characteristics as well as study procedures may account for these discrepancies: 1) the study by Shields et al. included a larger proportions of patients with bacteremia and pneumonia which are characterized by high bacterial burdens; 2) we included patients with infections caused by a variety of pathogens vs. only CRE infections in the Shields, et al study; and 3) repeat susceptibility testing was performed in less than one-third of our patients (30.0%). This study has several important limitations including its retrospective, observational design. Additionally, although this represents one of the largest studies to date evaluating the use of CZA for MDR infections, the sample size was still relatively small, limiting our ability to conduct meaningful subgroup analyses. The use of rapid diagnostics varied across centers and CZA susceptibility testing Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 was performed on a relatively small proportion of isolates. We also did not have data regarding the mechanisms responsible for resistance. However, this is unfortunately reflective of real-world practice where, as noted previously, validated susceptibility testing methods often lag antibiotic approvals. Finally, the interpretation of CZA effectiveness and safety is limited by the lack of a control group. Comparative outcomes research of newer antibiotics is desperately needed. Indeed one may reasonably argue that there is no longer equipoise with regards to the comparative safety 12, 15, 32, 33 and efficacy of older more toxic regimens and newly approved CRE-active agents. Clinicians and patients would be better served if regulatory bodies would revise their guidance to the industry to stipulate that agents in late stage development targeted to MDR pathogens be compared to the new standard. In conclusion, our study adds to the growing body of literature describing CZA treatment patterns and outcomes for MDR infections. Our study shows that when patients are managed by infectious diseases physicians, CZA can be an effective therapy for MDR Pseudomonas as well as CRE infections. We provide additional data that should prompt clinicians to reassess the anticipated benefits and risks of combination therapy in the era of novel gram-negative agents. Our study also highlights the need for continued advances to improve outcomes in vulnerable patient groups including those with MDR gram-negative bacteremia or pneumonia and patients with severe renal impairment. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Acknowledgements This study has been presented, in part, at ID Week October 3 -7, 2018 San Francisco, CA (abstract 2379), ASM Microbe June 20 - 24, 2019, San Francisco, CA (abstract CIV-142) and ID Week October 1 – 6, 2019, Washington, DC (abstract 2254). Funding This study was funded by an investigator initiated grant from Allergan. Disclosures MJR: Research support, consultant or speaker for Allergan, Melinta, Merck, Motif, Nabriva, Paratek, Tetraphase and Shionogi KCC: Ad hoc board for Melinta Therapeutics JRR: Consulting agreements or is on the speakers bureau with Allergan, Merck, Shinogi, Tetraphase, Melinta, Paratek SLD: Consultant for Allergan, Sperow and Tetraphase. SJE: Employee of T2 Biosystems Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 All other authors have nothing to disclose References 1. Munita JM, Aitken SL, Miller WR et al. Multicenter Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa. Clin Infect Dis 2017; 65: 158-61. 2. Doi Y, Bonomo RA, Hooper DC et al. Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group. Clin Infect Dis 2017; 64: S30-S5. 3. Munoz-Price LS, Poirel L, Bonomo RA et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013; 13: 785-96. 4. Benattar YD, Omar M, Zusman O et al. The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study. Clin Infect Dis 2016; 63: 1605-12. 5. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999; 43: 1003-12. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 6. Panidis D, Markantonis SL, Boutzouka E et al. Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Chest 2005; 128: 545-52. 7. Zasowski EJ, Rybak JM, Rybak MJ. The beta-Lactams Strike Back: Ceftazidime- Avibactam. Pharmacotherapy 2015; 35: 755-70. 8. Karlowsky JA, Biedenbach DJ, Kazmierczak KM et al. Activity of Ceftazidime- Avibactam against Extended-Spectrum- and AmpC beta-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014. Antimicrob Agents Chemother 2016; 60: 2849-57. 9. Nichols WW, de Jonge BL, Kazmierczak KM et al. In Vitro Susceptibility of Global Surveillance Isolates of Pseudomonas aeruginosa to Ceftazidime-Avibactam (INFORM 2012 to 2014). Antimicrob Agents Chemother 2016; 60: 4743-9. 10. Caston JJ, Lacort-Peralta I, Martin-Davila P et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis 2017; 59: 118-23. 11. King M, Heil E, Kuriakose S et al. Multicenter Study of Outcomes with Ceftazidime- Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2017; 61. 12. Shields RK, Nguyen MH, Chen L et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother 2017; 61. 13. Shields RK, Potoski BA, Haidar G et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem- Resistant Enterobacteriaceae Infections. Clin Infect Dis 2016; 63: 1615-8. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 14. Temkin E, Torre-Cisneros J, Beovic B et al. Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms. Antimicrob Agents Chemother 2017; 61. 15. van Duin D, Lok JJ, Earley M et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis 2018; 66: 163-71. 16. Shields RK, Nguyen MH, Chen L et al. Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 2018; 62. 17. Harris PA, Taylor R, Thielke R et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377-81. 18. Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-83. 19. Vincent JL, Moreno R, Takala J et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707-10. 20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41. 21. Evans SR HE, Doernberg S, Gouskova NA, Patillo S, Corey R, Boucher H, Fowler VG, Cosgrove SE, Chambers HF. Using endpoints to analyze patients rather than patients to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 analyze endpoints: a pre-trial substudy to develop a global outcome for clinical trials Society for Clinical Trials 37th Annual Meeting. Montreal, Quebec, Canada. 22. Abdul-Mutakabbir JC, Kebriaei R, Jorgensen SCJ et al. Teaching an Old Class New Tricks: A Novel Semi-Synthetic Aminoglycoside, Plazomicin. Infect Dis Ther 2019; 8: 155- 23. Heaney M, Mahoney MV, Gallagher JC. Eravacycline: The Tetracyclines Strike Back. Ann Pharmacother 2019: 1060028019850173. 24. Jorgensen SCJ, Rybak MJ. Meropenem and Vaborbactam: Stepping up the Battle against Carbapenem-resistant Enterobacteriaceae. Pharmacotherapy 2018; 38: 444-61. 25. Buehrle DJ, Shields RK, Chen L et al. Evaluation of the In Vitro Activity of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Meropenem-Resistant Pseudomonas aeruginosa Isolates. Antimicrob Agents Chemother 2016; 60: 3227-31. 26. Humphries RM, Hindler JA, Wong-Beringer A et al. Activity of Ceftolozane- Tazobactam and Ceftazidime-Avibactam against Beta-Lactam-Resistant Pseudomonas aeruginosa Isolates. Antimicrob Agents Chemother 2017; 61. 27. Alexander EL, Loutit J, Tumbarello M et al. Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials. Open Forum Infect Dis 2017; 4: ofx063. 28. Bonine NG, Berger A, Altincatal A et al. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status From Serious Gram-negative Bacterial Infections. Am J Med Sci 2019; 357: 103-10. 29. Seymour CW, Gesten F, Prescott HC et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med 2017; 376: 2235-44. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 30. Lodise TP, Jr., Patel N, Kwa A et al. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother 2007; 51: 3510-5. 31. Raman G, Avendano E, Berger S et al. Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis. BMC Infect Dis 2015; 15: 395. 32. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem- Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther 2018; 7: 439-55. 33. McKinnell JA, Dwyer JP, Talbot GH et al. Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae. N Engl J Med 2019; 380: 791-3. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 1: Demographic and clinical characteristics a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N= 117 N=63 Age, years 62 (49, 72) 63 (52, 73) 62 (43, 74) Age ≥ 65 years 90 (44.3) 53 (45.3) 28 (44.4) Male gender 39 (61.9) 63 (53.8) 39 (61.9) Race African American 93 (45.8) 57 (48.7) 30 (47.6) Caucasian 79 (38.9) 41 (35.0) 21 (33.3) Latino 8 (3.9) 6 (5.1) 3 (4.8) Other 22 (10.8) 13 (11.1) 9 (14.3) BMI 27 (22, 35) 27 (22, 34) 25 (21, 35) Obese (BMI ≥ 30 kg/m ) 77 (37.9) 40 (34.2) 23 (36.5) Estimated CrCl (mL/min) 65 (34, 105) 60 (29, 101) CrCl ≤ 30 mL/min 40 (19.7) 25 (21.4) 13 (20.6) CrCl 31-50 mL/min 28 (13.8) 14 (12.0) 10 (15.9) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 CrCl 51-90 mL/min 50 (24.6) 27 (23.1) 15 (23.8) CrCl 91 – 130 mL/min 28 (13.8) 18 (15.4) 7 (11.1) CrCl > 130 mL/min 27 (13.3) 13 (11.1) 11 (17.5) Hemodialysis 30 (14.8) 20 (17.1) 7 (11.1) Residence prior to admission Community 101 (49.8) 59 (50.4) 25 (39.7) SNF/LTAC 65 (32.0) 38 (32.5) 23 (11.3) Transferred from outside 28 (13.8) 14 (12.0) 11 (5.4) hospital Other 9 (4.4) 6 (3.0) 4 (2.0) Comorbid conditions Diabetes 85 (41.9) 46 (39.3) 33 (52.4) Heart Failure 37 (18.2) 20 (17.1) 12 (19.0) Chronic kidney disease 65 (32.0) 40 (34.2) 19 (30.2) Chronic lung disease 74 (36.5) 40 (34.2) 29 (46.0) Malignancy 27 (13.3) 19 (16.2) 6 (9.5) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Liver disease 21 (10.3) 15 (12.8) 2 (3.2) Charlson Comorbidity score 4 (2, 6) 4 (2, 7) 4 (2, 6) Charlson Comorbidity score > 4 85 (41.9) 51 (43.6) 25 (39.7) Immunocompromised 22 (10.8) 16 (13.7) 4 (6.3) MDRO infection or colonization 97 (47.8) 56 (47.9) 34 (54.0) within 1 year Recent antibiotic exposure 157 (77.3) 96 (82.1) 51 (81.0) (≥ 24 hours within 90 days) Recent hospitalization 151 (74.4) 94 (80.3) 46 (73.0) (≥ 48 hours within 90 days) Recent surgery 38 (18.7) 23 (19.7) 10 (15.9) (within 30 days) ICU at index culture 102 (50.2) 62 (53.0) 35 (55.6) SOFA score 5 (2, 8) 5 (2, 8) 5 (2, 8) a. All values represent number (%) or median (interquartile range) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 b. Estimated by using the Cockroft Gault equation ; creatinine measured within 24 hours of first dose ceftazidime-avibactam; BMI: body mass index; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; ICU: intensive care unit; LTAC: long-term acute care hospital; MDRO: multidrug-resistant organism; SOFA: Sequential Organ Failure Assessment; SNF: skilled nursing facility Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 2: Infection characteristics a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Hospital-acquired infection 117 (57.6) 71 (60.7) 38 (60.3) Hours from admission to culture 3 (2, 16) 6 (2, 17) 73 (2, 13) collection Infection Source Primary bacteremia 10 (4.9) 7 (6.0) 1 (1.6) Respiratory 76 (37.4) 39 (33.3) 38 (60.3) Intra-abdominal 38 (18.7) 26 (22.2) 3 (4.8) Skin and soft tissue 18 (8.9) 8 (8.8) 6 (9.5) Osteoarticular 14 (6.9) 7 (6.0) 6 (9.5) Urine 40 (19.7) 24 (20.4) 7 (11.1) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Prosthetic device 2 (1.0) 2 (1.7) 0 Intravenous catheter 4 (2.0) 3 (2.6) 2 (3.2) Other 1 (0.5) 1 (0.9) 0 Positive blood cultures 22 (10.8) 10 (8.5) 3 (4.8) Organism Enterobacteriacea 159 (78.3) 117 (100) Klebsiella pneumoniae 89 (43.8) 74 (63.2) K. oxytoca 8 (3.9) 5 (4.3) Escherichia coli 23 (11.3) 17 (14.5) Enterobacter spp. 29 (14.3) 15 (12.8) Proteus mirabilis 8 (3.9) 1 (0.9) Citrobacter spp. 9 (4.4) 5 (4.3) Serratia marcescens 6 (3.0) 4 (3.4) Providentia stuarti 4 (2.0) 0 Morganella morganii 4 (2.0) 0 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas spp. 63 (31.0) Acinetobacter spp. 12 (5.9) Stenotrophomonas maltophilia 5 (2.5) Gram-positive 30 (14.8) Polymicrobial infection 48 (23.6) 30 (25.6) 17 (27.0) K. pneumoniae CZA MIC (mg/L) MIC 1 1 MIC 2 4 N=51 N=43 P. aeruginosa CZA MIC (mg/L) MIC MIC 2 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 N=19 a. All values represent number (%) or median (interquartile range) b. Perinephric abscess c. Eleven of 12 patients had polymicrobial infections and received additional other antibiotics targeting Acinetobacter spp. The remaining patient had monomicrobial Acinetobacter UTI. They received CZA (surprisingly MIC 8 mg/ml) plus minocycline. The rationale for using CZA was not explicitly stated. d. All patients had polymicrobial infections and received additional other antibiotics targeting S. maltophilia CRE: carbapenem-resistant Enterobacteriaceae; CZA: ceftazidime-avibactam; MIC: minimum inhibitory concentration Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 3: Treatment information a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Infectious disease consult 199 (98.0) 117 (100) 59 (93.7) b c Time to infectious disease 28 (4, 63) 29 (9, 65) 24 (0, 86) consult (hours) Surgical consult 58 (28.6) 32 (27.4) 17 (27.0) Source control pursued 54 (26.6) 29 (24.8) 19 (30.2) Active antibiotic(s) before CZA 54 (26.6) 27 (23.1) 12 (19.0) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Time to active antibiotic(s) 55 (7, 102) 69 (26, 103) 72 (12, 123) (hours) Active antibiotic(s) within 48 91 (44.8) 39 (33.3) 24 (38.1) hours Time to CZA (hours) 85 (42, 146) 93 (52, 145) 94 (34, 170) CZA within 48 hours 59 (29.1) 25 (21.4) 17 (27.0) Renal CZA dose adjustment 92 (45.3) 54 (46.2) 28 (44.4) CZA combination therapy 68 (33.5) 45 (38.5) 20 (31.7) Aminoglycoside 21 (10.3) 13 (11.1) 8 (12.7) Colistin / polymyxin B 17 (8.4) 10 (8.5) 5 (7.9) Fluoroquinolone 10 (4.9) 8 (6.8) 2 (3.2) Tigecycline 16 (7.9) 10 (8.5) 3 (4.8) Minocycline 2 (1.0) 1 (0.9) 0 Aztreonam 3 (1.5) 1 (0.9) 2 (3.2) Inhaled antibiotic therapy in 19/76 (25.0) 7/39 (7.9) 14/38 (36.8) patients with a respiratory tract Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 infection CZA duration (days) 9 (6, 16) 13 (6, 18) 9 (5, 14) a. All values represent number (%) or median (interquartile range) b. N = 199 c. N = 59 d. Inhaled tobramycin or colistin CRE: carbapenem-resistant Enterobacteriaceae;; CZA: ceftazidime-avibactam Table 4: Outcomes a a a Total cohort CRE infection Pseudomonas spp. infection N = 203 N = 117 N = 63 Effectiveness Discharge disposition Home 57 (28.1) 31 (26.5) 16 (25.4) SNF/LTAC 90 (44.3) 53 (45.3) 32 (50.8) Inpatient rehabilitation 14 (6.9) 8 (6.8) 3 (4.8) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 facility Hospice 8 (3.9) 5 (4.3) 2 (3.2) In hospital mortality 34 (16.7) 20 (17.1) 10 (15.9) Discharge disposition among patients admitted from home Home 47 /101 (46.5) 25 / 59 (42.4) 11 / 25 (44.0) SNF/LTAC 29 /101 (28.7) 18 / 59 (30.5) 9 / 25 (36.0) Inpatient rehabilitation facility 10 /101 (9.9) 6 / 59 (10.2) 3/25 (12.0) Hospice In hospital mortality 2 /101 (2.0) 2/ 59 (3.4) 0 13 / 101 (12.9) 8 / 59 (13.6) 2/ 25 (8.0) Composite clinical failure 59 (29.1) 34 (29.1) 19 (30.2) 30-day mortality 35 (17.2) 19 (16.2) 11 (17.5) 30-day recurrence 12 (5.9) 7 (6.0) 4 (6.3) Worsen or failure to 32 (15.8) 18 (15.4) 12 (19.0) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 improve while on CZA Development of CZA resistance 0 0 0 (n=61) Safety Acute kidney injury 10/177 (5.6) 5/101 (5.0) 4/56 (7.1) Clostridioides difficile infection 3 (1.5) 3 (2.6) 0 Rash 2 (1.0) 0 2 (3.2) a. All values represent number (%) or median (interquartile range) b. Evaluated in patients with follow-up cultures c. Patients receiving hemodialysis excluded CRE: carbapenem-resistant Enterobacteriaceae; CZA: ceftazidime-avibactam Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Table 5: Multivariable logistic regression model for clinical failure Variable Adjusted odds ratio (95% CI) P value Primary bacteremia or respiratory tract 2.270 (1.115, 4.620) < 0.001 infection SOFA score 1.234 (1.118, 1.362) 0.0238 CZA within 48 hours of culture collection 0.409 (0.180, 0.930) 0.0329 a. Variable considered for model entry were: admission from an outside hospital, CrCl ≤ 30 mL/min or receipt of hemodialysis, previous hospitalization within 90 days, hospital-acquired infection, primary bacteremia or respiratory tract infection, pursuit of source control, early (≤ 48 hours) active antibiotic therapy, early (≤ 48 hours) CZA, APACHE II score, SOFA score, ICU at infection onset APACHE: Acute Physiological and Chronic Health Evaluation; CI: confidence interval; CrCl: creatinine clearance; CZA: ceftzidime-avibactam; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Supplementary Appendix 1 Carbapenem-resistant Klebsiella pneumoniae antibiogram Organism Percent susceptible Ceftazidime- Amikacin Gentamicin Colistin Tigecycine Meropenem avibactam CR-K. pneumoniae 96.0% 66.7% 65.7% 100.0% 64.4% 14.5% N=50 N=33 N=70 N=44 N=45 N=62 a. Clinical and Laboratory Standards Institute (CLSI) 2019 breakpoints used for all antibiotics except colistin for which the EUCAST breakpoint of 2 mg/mL was applied CR: carbapenem-resistant Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Pseudomonas aeruginosa antibiogram Organism Percent susceptible Ceftazidime- Ceftolozane- Amikacin Tobramycin Ceftazidime Piperacillin- Meropenem avibactam tazobactam tazobactam Pseudomonas 92.6% 85.2% 94.0% 78.0% 52.5% 28.0% 22.5% aeruginosa N=27 N=27 N=50 N=50 N=40 N=50 N=49 a. Clinical and Laboratory Standards Institute (CLSI) 2019 breakpoints used for all antibiotics Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Supplementary Appendix 2 Univariate analyses for clinical failure a a Clinical success Clinical failure Odds ratio (95% CI) P value N=144 N=59 Age, years 0.989 (0.972, 1.008) 0.251 Age ≥ 65 years 69 (47.9) 21 (35.6) 0.601 (0.321, 1.122) 0.109 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Male gender 80 (55.6) 31 (52.5) 0.886 (0.482, 1.626) 0.695 African American 61 (42.4) 32 (54.2) 1.613 (0.877, 2.967) 0.123 BMI 1.025 (0.994, 1.057) 0.118 Obese (BMI ≥ 30 kg/m ) 51 (35.4) 26 (44.1) 1.437 (0.775, 2.663) 0.249 Estimated CrCl (mL/min) CrCl ≤ 30 mL/min 26 (18.1) 14 (23.7) 1.615 (0.552, 4.729) 0.382 CrCl 31-50 mL/min 24 (16.7) 4 (6.8) 0.500 (0.128, 1.950) 0.318 CrCl 51-90 mL/min 36 (25.0) 14 (23.7) 1.167 (0.406, 3.350) 0.775 CrCl 91 – 130 mL/min 21 (14.6) 7 (11.9) Reference --- CrCl > 130 mL/min 20 (13.9) 7 (11.9) 1.050 (0.312, 3.533) 0.937 Hemodialysis 17 (11.8) 13 (22.0) 2.294 (0.749, 7.027) 0.146 CrCl ≤ 30 mL/min or hemodialysis 43 (29.9) 27 (45.8) 1.982 (1.062, 3.700) 0.030 Residence prior to admission Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Community 74 (51.4) 27 (45.8) Reference --- SNF/LTAC 47 (32.6) 18 (30.5) 1.050 (0.521, 2.113) 0.892 Transferred from 16 (11.1) 12 (20.3) 2.056 (0.862, 4.899) 0.104 outside hospital Other 7 (4.9) 2 (3.4) 0.783 (0.153, 4.005) 0.769 Comorbid conditions Diabetes 60 (41.7) 25 (42.4) 1.029 (0.557, 1.901) 0.926 Heart Failure 25 (17.4) 12 (20.3) 1.215 (0.565, 2.616 0.618 Chronic kidney 41 (28.5) 24 (40.7) 1.723 (0.915, 3.244) 0.091 disease Chronic lung disease Malignancy 15 (10.4) 6 (10.2) 0.974 (0.358, 2.645) 0.958 Liver disease 20 (13.9) 7 (11.9) 0.835 (0.333, 2.094) 0.700 Charlson Comorbidity score 1.051 (0.947, 1.168) 0.349 Charlson Comorbidity score > 57 (39.6) 28 (47.5) 1.379 (0.749, 2.538) 0.302 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Immunocompromised 13 (9.0) 9 (15.3) 1.814 (0.730, 4507) 0.195 MDRO infection or 70 (48.6) 27 (45.8) 0.892 (0.486, 1.638) 0.712 colonization within 1 year Recent antibiotic exposure 108 (75.0) 49 (83.1) 1.633 (0.750, 3.555) 0.213 (≥ 24 h within 90 days) Recent hospitalization (≥ 48 101 (70.1) 50 (84.7) 2.365 (1.069, 5.234) 0.030 hours within 90 days) Recent surgery (within 30 28 (19.4) 10 (16.9) 0.845 (0.382, 1.873) 0.679 days) ICU at index culture 62 (43.1) 40 (67.8) 2.784 (1.471, 5.270) 0.001 SOFA score 1.264 (1.155, 1.385) < 0.001 Hospital-acquired infection 74 (51.4) 43 (72.9) 2.542 (1.313, 4.921) 0.005 Infection Source Primary bacteremia 3 (2.1) 7 (11.9) Respiratory 44 (30.6) 32 (54.2) Intra-abdominal 33 (22.9) 5 (8.5) Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 Skin and soft tissue 13 (9.0) 5 (8.5) Osteoarticular 12 (8.3) 2 (3.4) Urine 34 (23.6) 6 (10.2) Prosthetic device 2 (1.4) 0 Intravenous catheter 2 (1.4) 2 (3.4) Other 1 (0.7) 0 Primary bacteremia or 47 (32.6) 39 (66.1) 4.024 (2.118, 7.646) < 0.001 respiratory tract infection Positive blood cultures 13 (9.0) 9 (15.3) 1.814 (0.730, 4.507) 0.195 Secondary bacteremia 10 (6.9) 2 (3.4) 0.470 (0.100, 2.214) 0.515 CRE 83 (57.6) 34 (57.6) 1.000 (0.541, 1.845) 0.999 Pseudomonas spp. 44 (30.6) 19 (32.2) 1.080 (0.563, 2.070) 0.818 Polymicrobial infection 34 (23.6) 14 (23.7) 1.007 (0.494, 2.052) 0.986 Treatment information Infectious disease consult 140 (97.2) 59 (100.0) 1.421 (1.299, 1.556) 0.325 Time to infectious diseases 1.000 (0.999, 1.001) 0.674 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 consult Infectious diseases consult ≤ 96 (68.6) 40 (67.8) 0.965 (0.503, 1.853) 0.915 48 hours after culture collection Surgical consult 42 (29.2) 16 (27.1) 0.904 (0.459, 1.779) 0.769 Source control pursued 44 (30.6) 10 (16.9) 0.464 (0.215, 0.999) 0.046 Active antibiotic(s) before 38 (26.4) 16 (27.1) 1.038 (0.524, 2.005) 0.915 CZA Time to active antibiotic(s) 1.000 (0.998, 1.002) 0.682 (hours) Active antibiotic therapy ≤ 48 71 (49.3) 20 (33.9) 0.527 (0.281, 0.990) 0.045 hours after culture collection Time to CZA (h) 1.001 (0.999, 1.002) 0.603 CZA within 48 hour 48 (33.3) 11 (18.6) 0.458 (2.18, 0.962) 0.036 CZA within 72 hours 64 (44.4) 23 (39.0) 0.799 (0.431, 1.481) 0.475 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz522/5660961 by DeepDyve user on 06 December 2019 CZA within 96 hours 83 (57.6) 29 (49.2) 0.710 (0.387, 1.305) 0.270 CZA within 120 hours 100 (69.4) 36 (61.0) 0.689 (0.366, 1.296) 0.246 Combination IV antibiotic 44 (30.6) 24 (40.7) 1.558 (0.831, 2.923) 0.165 therapy with CZA Inhaled antibiotic therapy 10 (6.9) 11 (18.6) 3.071 (1.227, 7.687) 0.013 CZA renal dose adjustment 61 (42.4) 31 (52.5) 1.506 (0.820, 2.769) 0.186 a. All values represent number (%) or median (interquartile range) b. N = 199 BMI: body mass index; CI: confidence interval; CRE: carbapenem-resistant Enterobacteriaceae; CrCl: creatinine clearance; CZA: ceftazidime-avibactam; ICU: intensive care unit; LTAC: long-term acute care hospital; MDRO: multidrug-resistant organism; SOFA: Sequential Organ Failure Assessment; SNF: skilled nursing facility Accepted Manuscript

Journal

Open Forum Infectious DiseasesOxford University Press

Published: Dec 1, 2019

There are no references for this article.