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Ceftaroline Fosamil (CPT) Versus DAP Plus Sulfamethoxazole/ Trimethoprim (SMX/TMP) for Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections (BSI) Evan J

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Ceftaroline Fosamil (CPT) Versus DAP Plus Sulfamethoxazole/ Trimethoprim (SMX/TMP) for Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections (BSI) Evan J Retrospective Evaluation of Daptomycin (DAP) plus Ceftaroline fosamil (CPT) versus DAP plus Sulfamethoxazole/ Trimethoprim (SMX/TMP) for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections (BSI) Evan J. Zasowski, Pharm.D., BCPS1, Kimberly C. Claeys, Pharm.D.1, Karrine D. Roberts, Pharm.D.2,Donald P. Levine, M.D.3, Susan L. Davis, Pharm.D.1,4, Michael J. Rybak, Pharm.D., M.P.H.1, 3 Address correspondence to: ECCMID 2015 1. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit MI, USA; 2. Department of Pharmacy Services, Detroit Medical Center, Detroit, MI, USA ; P0700 Michael J. Rybak, Pharm.D., M.P.H. 3. Department of Medicine, Division of Infectious Diseases, School of Medicine, Wayne State University, Detroit, MI, USA; 4. Henry Ford Health System, Detroit, MI, USA [email protected] Introduction and Purpose Results • Clinical failure rates and emergence of resistance to first and second- Table 1. Baseline and clinical characteristics Figure 2. Line of therapy* of combination regimen Table 2. Clinical outcomes line treatments for methicillin-resistant Staphylococcus aureus DAP + CPT DAP + SMX/TMP Characteristic p-value 100 DAP + CPT DAP + SMX/TMP N = 23 N = 16 Outcome p-value (MRSA) bloodstream infections (BSI) has led to the exploration of 90 N = 23 N = 16 novel alternative antibiotic treatment strategies Demographics and Comorbid Conditions! 80 Composite failure, n (%)! 7 (30.4)! 7 (43.8)! 0.39! Age, mean (SD)! 57.9 (12.5)! 49.7 (10.8)! 0.04a! 70 30-day mortality, n (%)! 2 (8.7)! 2 (12.5)! 1! Male, n (%)! 18 (78.3)! 11 (68.8)! 0.71! • Two such novel combination regimens which have shown promise are 60 BSI ≥ 7 days on combination, n (%)! 3 (13.0)! 2 (12.5)! 1! African American, n (%)! 21 (91.3)! 16 (100)! 0.50! Recurrence within 60 days, n (%)! 3 (13.0)! 3 (18.8)! 0.67! daptomycin (DAP) + ceftaroline fosamil (CPT) and DAP + a 50 DAP + CPT Chronic kidney disease, n (%)! 15 (65.6)! 6 (37.5)! 0.04 ! Emergent resistance on combo, n (%)! 1 (4.3)! 0! 1! 1-4 40 sulfamethoxazole/trimethoprim (SMX/TMP) ESRD on renal replacement therapy, n (%)! 9 (39.1)! 5 (31.3)! 0.61! DAP + SMX/TMP Hospital-LOS post-combo, median (IQR)! 13 (7,30)! 17 (7.5,28)! 0.77! Liver disease, n (%)! 8 (34.8)! 7 (43.8)! 0.57! Percentage 30 Duration BSI post-combo, median (IQR)! 2 (1,5)! 2 (1,4.8)! 0.81! • Data surrounding these combinations is currently limited to in vitro Diabetes mellitus, n (%)! 9 (39.1)! 4 (25.0)! 0.36! 20 Inpatient Adverse drug reaction, n (%)! 1 (4.3)! 5 (31.3)! 0.03 ! experiments and descriptive case series, and no comparative clinical Cerebrovascular accident, n (%)! 4 (17.4)! 4 (25.0)! 0.69! 10 Creatine phosphokinase (CPK) elevation, n (%)! 1 (4.3)! 3 (18.8)! 0.29! IVDU, n (%)! 8 (34.8)! 6 (37.5)! 0.86! 0 Hyperkalemia, n (%)! 0! 2 (12.5)! 0.16! data exist Obesity, n (%)! 1 (4.3)! 2 (12.5)! 0.56! 2nd line 3rd line 4th line Neutropenia, n (%)! 0! 0! 1! Prior antibiotics (30 days), n (%)! 10 (43.5)! 4 (25.0)! 0.24! * 1st line: initial regimen directed at MRSA BSI, 2nd line: second regimen directed at MRSA BSI, etc. a Defined as increase in CPK to > 1000 U/L; b Defined as increase in K to > the upper limit of normal ; c Defined as decrease in absolute • The objective of this analysis was to compare the clinical Prior MRSA infection (1 year), n (%) 7 (30.4)! 3 (18.8)! 0.48! No statistically differences in line of therapy between groups was observed neutrophil count (ANC) to < 1,500 cells/mm3 or ≥ 50% decline from initiation of study medication if baseline ANC < 1,500 cells/mm3 characteristics and outcomes of patients with MRSA BSI who were Infection and Clinical Characteristics! Skin/Soft tissue, n (%)! 1 (4.3)! 1 (6.3)! 1! treated with DAP + CPT or DAP + SMX/TMP Deep abscess, n (%)! 9 (39.1)! 7 (43.8)! 0.77! Figure 3. Kaplan-Meier curves of time to BSI clearance post-combo Figure 4. Clinical success rate among sources with at least 5 cases per group Bone/Joint, n (%)! 7 (30.4)! 6 (37.5)! 0.65! Infective endocarditis, n (%)! 8 (34.8)! 5 (31.3)! 0.82! 100 Methods Central nervous system, n (%)! 0! 1 (6.3)! 0.41! Pneumonia, n (%)! 2 (8.7)! 0! 0.50! DAP + CPT 90 • Single center, retrospective, cohort study completed at the Detroit IV catheter, n (%)! 1 (4.3)! 1 (6.3)! 1! DAP + SMX/TMP 80 Unknown, n (%)! 3 (13.0)! 1 (6.3)! 0.63! Medical Center from January 2011 to April 2015 bacteremic 70 VISA, n (%)! 0! 1 (6.3)! 0.41! • Inclusion: age ≥ 18; ≥ one positive blood culture for MRSA; received Daptomycin non-susceptible, n (%)! 4 (17.4)! 2 (12.5)! 1! 60 ICU admission, n (%)! 11 (47.8)! 7 (43.8)! 0.80! 50 DAP + CPT DAP + CPT, or DAP + SMX/TMP for ≥ 72 hours for MRSA BSI SOFA score at index culture, median (IQR)! 3.5 (1,5)! 3.5 (1.25,5)! 1! DAP + SMX/TMP Duration BSI pre-combo, median (IQR) 7 (4,10) 8 (6.25,11.25) 0.44 40 • Exclusions: BSI clearance prior to study therapy; prophylactic doses ! ! ! ! Percentage ID consult, n (%)! 23 (100)! 15 (93.8)! 0.41! 30 of SMX/TMP Treatment Information 20 Source control pursued, n (%)! 9 (39.1)! 8 (50.0)! 0.50! Combo initiation • The primary outcome was composite treatment failure: 30-day Daptomycin dose (mg/kg), median (IQR)! 10 (9.1,10)! 9.6 (8.8,10.3)! 0.87! remaining Proportion 10 mortality; failure to clear BSI within 7 days of initiation of study SMX/TMP dose (mg TMP), median (IQR)! -! 320 (195,320)! -! 0 Ceftaroline Q8H, n (%)! 12 (52.2)! -! -! Time (days) Overall Deep abscess IE Bone/joint therapy; recurrence of MRSA BSI within 60 days Inpatient duration of combo, median (IQR)! 8.5 (7,17.3)! 8.5 (5,16.8)! 0.78! No statistically difference in time to BSI clearance was observed No statistically differences in clinical success were observed between groups were observed ESRD: end stage renal disease; IVDU: intravenous drug user; VISA: vancomycin-intermediate Staphylococcus aureus; ICU: intensive care unit; SOFA: • Secondary outcomes: each component of composite failure; duration sequential organ failure assessment; a Were not associated with overall composite failure or any individual component of composite failure of BSI and hospital-length of stay (LOS) after initiation of Figure 1. Reason for combination therapy per medical team Conclusions combination; emergence of resistance after initiation of combination therapy, and inpatient adverse reactions (ADR) attributed to study DAP + CPT DAP + SMX/TMP Persistence • Clinical success was numerically higher among patients receiving DAP + CPT and the incidence of inpatient ADRs was treatment by medical team Persistence significantly higher among patients receiving DAP + SMX/TMP Resistance • Chi-squared or Fisher’s exact test, and Student’s t-test or Mann- • These results should be interpreted with great caution due to the retrospective nature of the study, limited sample size, Resistance Whitney U test were used in bivariate analysis where appropriate Pulmonary and inability to determine the incidence of ADRs following hospital discharge coverage • Time to BSI clearance was assessed through Kaplan-Meier Pulmonary • Preliminary results suggest that both DAP + CPT and DAP + SMX/TMP are viable options for MRSA BSI, including coverage Recurrence estimation recurrent or refractory cases with deep-seated sources and those caused by daptomycin non-susceptible isolates Recurrence References Other • Clearance of BSI following initiation of combination therapy was rapid in both treatment groups in a majority of subjects 1. Steed ME, et al. Antimicrob Agents Chemother. Nov 2012;56(11):5709-5714. Other • Further study is needed to delineate which patients would benefit from the use of combination therapy and determine the 2. Werth BJ, et al. Antimicrob Agents Chemother. Jun 2014;58(6):3177-3181. Not documented 3. Sakoulas G, et al. Clinical therapeutics. Jul 10 2014. optimal combination therapy for MRSA BSI 4. Claeys KC, et al. Antimicrob Agents Chemother. Apr 2015;59(4):1969-1976. No statistically differences in reason for combination therapy between groups was observed .
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