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Case Presentation – January 28th, 2015 Brian Skinner, PharmD PGY-1 Pharmacy Resident St. Vincent Indianapolis Hospital Patient Case JD is a 62yoM presenting to St. Vincent Hospital with altered mental status, lethargy, and fever PMH: Meningioma s/p resection 10/2015. Patient developed a CSF leak and had a VP shunt placed Developed shunt infection in October due to infection with Enterobacter cloacae Treated with cefepime IV 1g q 8 hours Patient Case Home Medications Acetaminophen 650mg po q 6 hour PRN Aspirin 81mg po daily Calcium 600+D po daily Dexamethasone 2mg po daily Divalproex sodium ER 1000mg po daily Famotidine 20mg po BID Glipizide ER 5mg po daily Hydrocodone/APAP 5/325 po q 4 hours PRN pain Milk of Magnesia 30mL po daily PRN Ondansetron 4mg po q 8 hour PRN nausea Simvastatin 20mg po daily Patient Case 140 99 15 4.3 29 0.71 145 10.1 12.4 38.4 CSF Fluid Analysis Color Colorless Appearance Clear RBC WBC Glucose T. Protein 11 67 49 59 273 Clinical Course Empiric Therapy Cefepime 2g IV q 8 + Vancomycin 1g IV q 12 Meningiomas Largest subgroup of all intracranial tumors Usually benign, slow growing neoplasms Surgical resection is common therapy Radiation can be used if incomplete resection Forum (Genova). 2003;13(1):76-89. VP Shunts Derived from the Middle English word shun Diverts CSF fluid from ventricles to peritoneum Various shunts are available Nomenclature is based on where it drains Ventricular Shunting Procedures. In: Youmans Neurological Surgery. 6th ed. 2011. VP Shunts – Complications Intraventricular hemorrhage Obstruction Over drainage of CSF Infection AACN Adv Crit Care. 2013;24(1)6-12. CSF Shunt & Drain Infections. In: Principles & Practice of Infectious Disease. 8th ed. 2015. Etiology of Infection Most Common Coagulase negative Staphylococci spp. Staphylococcus aureus Other Etiologies Candida albicans Corynebacterium jeikeium Streptococcus spp. Mycobacterium spp. Pseudomonas aeruginosa Stenotrophomonus spp. Clin Infect Dis. 2004;39:1267-84. AACN Adv Crit Care. 2013;24(1)6-12. CSF Shunt & Drain Infections. In: Principles & Practice of Infectious Disease. 8th ed. 2015. Empiric Treatment Options Microorganism Coag-negative Staph. spp. & MRSA Antibiotic Vancomycin Dosing 15mg/kg every 812 hours Gram-negative Bacilli (including Pseudomonas spp.) Ceftazidine 2g every 8 hours Cefepime 2g every 8 hours Meropenem 2g every 8 hours N Engl J Med. 2010;362:146-54. Clin Infect Dis. 2004;39:1267-84. AACN Adv Crit Care. 2013;24(1)6-12. Susceptibility Data β -Lactamase Production First “penicillinase” discovered in 1940 in E. coli AmpC β-lactamase has been found in a variety of organisms Chromosomal AmpC Plasmid AmpC Clin Microbio Rev. 2009;22(1):161-182. Verigene® Antimicrob Agents Chemother. 2010;54(3):969-976. AmpC β-lactamase Induction B-Lactam Antibiotic Penicillin, aminopenicillins, cefazolin Inducer? Strong Substrate? Good Cefotaxime, ceftriaxone, ceftazidime, cefepime Cefoxitin, Imipenem Weak Poor Strong Poor Induction involves a complex chemical pathway that results in hyperproduction of AmpC β-lactamase Binding of β-lactam antibiotic prevents synthesis of intracellular compounds that “turn off” AmpC β-lactamase production Clin Microbio Rev. 2009;22(1):161-182. Inducibility Most cases reported in the context of Enterobacter spp. Informally labeled “ESCPM” group Enterobacter spp. Serratia spp. Citrobacter spp. Providencia spp. Morganella spp. Clin Microbio Rev. 2009;22(1):161-182. Eur J Clin Microbiol. 1987;6(4)439-445. Stable Derepression of AmpC Production Permanent hyperproduction of AmpC βlactamase Antibiotic use selectively allows depressed mutants to proliferate Clin Microbio Rev. 2009;22(1):161-182 Stable Derepression of AmpC Production Ann Intern Med. 1991;115(8): 585-590. Cefepime and AmpC Cefepime is structurally similar to ceftazidime, but has decreased susceptibility to AmpC β-lactamases In vitro activity of 995 isolates in Australia showed comparable susceptibilities to carbapenems against AmpC-producing species Int J Antimicrob Agents. 2013;41:236-49. Int J Antimicrob Agents. 2012;40:297-305. Cefepime and AmpC Antibiotic Ceftriaxone Cefepime Pip/Tazo Meropenem Ciprofloxacin Total Responders 4 (47.1%) 16 (88.9%) 5 (71.4%) 11 (100%) 6 (100%) 43 (84.3%) Non-responders 3 (42.9%) 2 (11.1%) 2 (28.6%) 0 (0%) 0 (0%) 8 (15.7%) “…the clinical data proved that cefepime is a reasonable alternative to carbapenems” for blood stream infections caused by Enterobacter cloacae Int J Antimicrob Agents. 2013;41:236-49. Cefepime and AmpC Inoculum effect Significant MIC increase when microbial population size is increased Case reports of treatment failure have been seen in patient’s with a high inoculum infection J Antimicrob Chemother. 2004;54:1130-33 Carbapenems and Valproate Significant interaction exists between valproic acid and carbapenem antibiotics Administration of carbapenems remarkably decreases serum concentrations of valproate Mechanism of interaction is not well defined Interaction can not be overcome by additional valproate administration Ther Drug Monit. 2012;34:599-603 Carbapenems and Valproate Design • Retrospective study of patients receiving carbapenem antibiotics and VPA from 2008-2010 Inclusion Criteria • Received VPA to control or prevent seizures • Had VPA concentrations checked regularly • Received a carbapenem antibiotic Exclusion Criteria • Stopped VPA before receiving carbapenem antibiotics • Use of drugs known to interact with VPA Ther Drug Monit. 2012;34:599-603 Results Ther Drug Monit. 2012;34:599-603 Patient Case Shunt was externalized and changed to VP drain Divalproex was changed to levetiracetam 500mg po BID 4 days after starting meropenem, CSF cultures were negative VP shunt was replaced 8 days after negative culture Patient was discharged 3 days after shunt replacement and will continue meropenem for an additional 6 days as at an acute rehab facility Clinical Course Empiric Therapy Cefepime 2g IV q 8 + Vancomycin 1g IV q 12 Day 3: E. cloacae positive culture Ceftriaxone 1g IV q 12 Day 4 Cefepime 2g IV q 8 Day 17: E. cloacae positive culture Meropenem 2g IV q 8 Case Presentation – January 28th, 2015 Brian Skinner, PharmD PGY-1 Pharmacy Resident St. Vincent Indianapolis Hospital