5/5/2015 Cefoxitin monotherapy versus cefoxitin-metronidazole combination therapy for the treatment of community-acquired intra-abdominal infection Jennifer Dela-Pena, PharmD PGY1 Pharmacy Resident Detroit Medical Center, Harper University Hospital Intra-abdominal Infections • Associated with morbidity and mortality – Mortality rate: 8.7% – 32% • Second most common infection in ICU • 80% are community-acquired intraabdominal infections (CA-IAI) • 11 million hospital days for appendicitis Krobot K et al. Eur J Clin Microbiol Infect Dis. 2004; 23:682–687. Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333. Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164. The speaker has no actual or potential conflicts of interest in relation to this presentation. Types of CA-IAI Common Organisms in CA-IAI Enterobacteriaceae Appendicitis Pancreatitis Diverticulitis Peritonitis Cholecystitis Cholangitis Streptococcus spp. Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333. Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333. Management: 2010 IDSA Guidelines Source Control Management IDSA = Infectious Diseases Society of America Antimicrobial Therapy Source Control Antimicrobial Therapy Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164. Anaerobes (Bacteroides spp.) Management: Source Control • Eliminate infectious foci through surgical interventions - Abscess drainage - Removal of necrotic tissue • Control factors that increase infection risk Management Source Control Antimicrobial Therapy Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164. 1 5/5/2015 Management: Source Control Publication Kind of Inflammation Number of Patients Initial Source Control Not Successful Management: Antimicrobial Therapy Mortality Seiler et al. Diffuse peritonitis 258 11% 27% (vs. 13%) Anderson et al. Severe intraabdominal sepsis 125 48% 90.2% (vs. 19.2%) Buchler et al. Diffuse peritonitis 186 11% 25% (vs. 10%) Wacha et al. Diffuse peritonitis 355 30% 47% (vs. 14%) • Impact of appropriate empiric antimicrobial therapy in CA-IAI – Increased clinical success • Step-down to oral therapy • Resolution of infection – Decreased duration of hospitalization Management Management Source Control Source Control Antimicrobial Therapy Hecker A et al. Langenbecks Arch Surg. 2014;399(1):11-22. 2010 IDSA Complicated Intra-abdominal Guidelines Monotherapy • • • • • Bacteroides Resistance to Cefoxitin United States Percent Resistance to Cefoxitin 2006-2009 Combination Therapy with Metronidazole Cefoxitin Ertapenem Moxifloxacin Tigecycline Ticarcillin-clavulanic acid • • • • • • IDSA = Infectious Diseases Society of America Cefazolin Cefuroxime Ceftriaxone Cefotaxime Ciprofloxacin Levofloxacin Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164. Detroit Medical Center Antibiogram 2 16 MEROPENEM 8+4 METRONIDAZOLE MIC < mcg/ml NO. OF ISOLATES CEFOXTIN ORGANISM CLINDAMYCIN AMPICILLIN SULBACTAM ANAEROBIC BACTERIA Antimicrobial Therapy Bare M et al. Int J Technol Assess Health Care. 2006;22(2):242-248. Krobot K et al. Eur J Clin Microbiol Infect Dis. 2004; 23:682–687. Nguyen M et al. Clin Infectious Dis. 2000; 30: 870-876. 8 # of isolates 2006-2007 (%) B. fragilis 1021 4.3 2008-2009 (%) 7.3 B. thetaiotaomicron 418 9.6 20.9 B. ovatus 153 15 14.1 B. vulgatus 136 4.5 5.8 B. distasonis 99 6.5 16.6 B. uniformis 67 13.4 7.1 Other Bacteroides spp. 63 4.3 8 Snydman DR et al. Anaerobe. 2011;17(4):147-151. Detroit Medical Center Guidelines CA-IAI Empiric Therapy 4 PERCENT SUSCEPTIBLE BACTEROIDES FRAGILIS 30 93 43 73 100 92 BACTEROIDES SPECIES 42 91 38 41 98 100 FUSOBACTERIUM SPECIES 15 100 100 93 100 89 PREVOTELLA SPECIES 11 91 82 91 100 -- Cefoxitin ± Metronidazole 2 5/5/2015 Methods Purpose • To evaluate clinical outcomes in patients who received cefoxitin monotherapy or cefoxitin and metronidazole combination therapy for the treatment of CA-IAI Hypothesis • No significant differences in clinical outcomes between the treatment regimens Study Design • Retrospective, multi-site cohort study IRB Approval • Detroit Medical Center • Wayne State University Methods: Patient Eligibility Inclusion • Admission to DMC hospital between January 2010 and July 2014 • Age 18-89 years old • Cefoxitin or cefoxitin/ metronidazole therapy for CA-IAI Methods: Primary Outcomes Clinical Success • Absence of persisting or worsening signs of infection per treating physician Clinical Failure • Escalation of antimicrobial treatment • Worsening infection per treating physician • 30-day all-cause mortality Exclusion • Non-intra-abdominal source of infection • Healthcare-associated infection • Antibiotics other than study regimen on admission • Gram-negative aerobes resistant to cefoxitin Methods: Secondary Outcomes • • • • Duration of antimicrobial treatment Duration of hospitalization Admission to ICU Re-admission within 30 days related to initial infection 3 5/5/2015 Methods: Statistical Analysis Results: Study Population N=681 • 128 patients total to reach 80% power • Software: SPSS • Normality test performed on all data Patients Screened N = 131 – Descriptive statistics – Mann-Whitney U Test – Fisher's Exact Test – Chi-squared Test – P-value < 0.05 significant N=69 Cefoxitin Results: Baseline Characteristics Cefoxitin/ Metronidazole (N=62) P-value Age (yr) - median (IQR) 52 (43-59) 52 (44-60) NS Male gender - n (%) 30 (43.5) 34 (54.8) NS 41 (67.2) 15 (24.6) 0 (0.0) 5 (8.2) 35 (70.0) 9 (18.0) 2 (4.0) 4 (8.0) NS NS NS NS Caucasian African American Hispanic Other Excluded N=62 Cefoxitin/Metronidazole Results: Baseline Characteristics Cefoxitin (N=69) Race - n (%) N=550 Included IQR – Interquartile range Cefoxitin (N=69) Cefoxitin/ Metronidazole (N=62) P-value Charlson Index - median (IQR) Liver disease - n (%) CKD - n (%) Diabetes - n (%) MI - n (%) CHF - n (%) 0 (0-0) 1 (1.4) 2 (2.9) 1 (1.4) 0 (0) 0 (0) 0 (0-2) 0 (0) 2 (3.2) 1 (1.6) 1 (1.6) 1 (1.6) NS NS NS NS NS NS APACHE II - median (IQR) 4 (2-6) 4 (2-7) NS ID consult - n (%) 4 (5.8) 8 (12.9) NS Bacteremia - n (%) 1 (2.9) 2 (3.2) NS Abscess - n (%) 7 (10.1) 12 (19.4) NS IQR – Interquartile range Results: Day 1 of Infection Results: Source of CA-IAI Cefoxitin (N=69) Cefoxitin/ Metronidazole (N=62) P-value 80.2 (63.9-106.5) 65.7 (58.0-85.1) 0.009 WBC (per mm3) - median (IQR) 12.2 (9.5-14.7) 13.1 (10.6-16.9) NS Temp ( ̊C) - median (IQR) 37.2 (36.8-37.6) 37.3 (37.0-38.0) NS CrCl (ml/min) - median (IQR) Overall (N=131) Cefoxitin (N=69) Cefoxitin/ Metronidazole (N=62) Diverticulitis - n (%) 46 (35.1) 7 (10.1) 39 (62.9) Cholecystitis - n (%) 41 (31.3) 37 (53.6) 4 (6.5) Appendicitis - n (%) 25 (19.1) 15 (21.7) 10 (16.1) Pancreatitis - n (%) 10 (7.6) 6 (8.7) 4 (6.5) Other - n (%) 6 (4.6) 3 (4.3) 3 (4.8) Cholangitis - n (%) 3 (2.3) 1 (1.4) 2 (3.2) 4 5/5/2015 Results: Surgical Intervention Results: Cultures 91.3% n = 63 P < 0.001 Cultures 41.9% n = 26 No Cultures N=69 N=62 Results: Organisms in Cultures Primary Outcome: Clinical Success 98.6% n = 68 Cefoxitin (N=26) Cefoxitin/ Metronidazole (N=18) P-value No growth - n (%) 16 (61.5) 10 (55.6) NS Polymicrobial - n (%) 6 (23.1) 4 (22.2) NS E. coli - n (%) 4 (15.4) 4 (22.2) NS K. Pneumoniae - n (%) 1 (3.8) 2 (11.1) NS Streptococcus - n (%) 6 (23.1) 3 (16.7) NS Bacteroides - n (%) 6 (23.1) 4 (22.2) NS 0 (0) 2 (11.1) NS Other - n (%) 98.4% n = 61 P > 0.99 N=69 Primary Outcome: Clinical Failure Overall - n (%) Secondary Outcomes Cefoxitin (N=69) Cefoxitin/ Metronidazole (N=62) P-value 1 (1.4) 1 (1.6) NS Escalation of therapy - n (%) 1 (1.4) 1 (1.6) NS Worsening of symptoms - n (%) 1 (1.4) 1 (1.6) 0 (0) 0 (0) 30-day all-cause mortality - n (%) N=62 Cefoxitin (N=69) Duration of cefoxitin therapy (days) median (IQR) 2.9 (2.0-3.5) Cefoxitin/ Metronidazole P-value (N=62) 3.0 (2.3-4.9) NS Total duration of therapy (days) median (IQR) 3.6 (2.7-8.1) 10 (8.5-13.0) - Discharged on antibiotic - n (%) 26 (37) 46 (74) NS < 0.001 < 0.001 5 5/5/2015 Secondary Outcomes Cefoxitin (N=69) Admission to ICU - n (%) Discussion Cefoxitin/ Metronidazole (N=62) • Majority of patients did not have cultures P-value 0 (0) 1 (1.6) NS Length of stay (days) - median (IQR) 3.2 (2.5-4.7) 4.0 (2.6-5.2) 0.027 Re-admission within 30 days - n (%) 2 (2.9) 4 (6.5) NS – Cultures not necessary in CA-IAI if therapy active against common organisms – Change in therapy not required if clinical response occurs Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164. Discussion Limitations • Cefoxitin/Metronidazole therapy • • • • – Feasibility of source control based on type of CA-IAI – More likely to be discharged on antibiotic – Longer duration of therapy Retrospective Diagnosis per treating physician Intra-operative antibiotics documentation Lack of susceptibility testing for anaerobes Conclusion Future Directions • No significant differences in clinical outcomes between monotherapy and combination therapy • Addition of metronidazole to cefoxitin not warranted for empiric treatment of CA-IAI • Re-assess DMC CA-IAI empiric guidelines for combination therapy • Cefoxitin/Metronidazole therapy – Short vs. long duration 6 5/5/2015 Learning Question #1 Learning Question #1 1. Which organisms are most commonly associated with community-acquired intraabdominal infections? 1. Which organisms are most commonly associated with community-acquired intraabdominal infections? A. Enterobacteriacae, Staphylococcus aureus and Enterococcus faecalis B. Enterobacteriacae, Streptococcus spp. and anaerobes C. Staphylococcus aureus, Enterococcus faecalis and anaerobic organisms D. Streptococcus spp., Enterococcus faecalis, Stenotrophomonas maltophilia A. Enterobacteriacae, Staphylococcus aureus and Enterococcus faecalis B. Enterobacteriacae, Streptococcus spp. and anaerobes C. Staphylococcus aureus, Enterococcus faecalis and anaerobic organisms D. Streptococcus spp., Enterococcus faecalis, Stenotrophomonas maltophilia Learning Question #2 Learning Question #2 2. According to the 2010 Infectious Diseases Society of America guidelines, which of the following can be used as initial empiric monotherapy of CA-IAI? 2. According to the 2010 Infectious Diseases Society of America guidelines, which of the following can be used as initial empiric monotherapy of CA-IAI? A. moxifloxacin B. ceftriaxone C. cefazolin D. levofloxacin Acknowledgements Kyle Murray, PharmD, BCPS Clinical Pharmacist Specialist Infectious Diseases and Critical Care Huron Valley-Sinai Hospital Commerce Township, MI Jing Zhao, PharmD Clinical Pharmacist Specialist Infectious Diseases Harper University Hospital Detroit, MI A. moxifloxacin B. ceftriaxone C. cefazolin D. levofloxacin Cefoxitin monotherapy versus cefoxitin-metronidazole combination therapy for the treatment of community-acquired intra-abdominal infection Jennifer Dela-Pena, PharmD PGY1 Pharmacy Resident Detroit Medical Center, Harper University Hospital The speaker has no actual or potential conflicts of interest in relation to this presentation. 7
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