Ventriculoperitoneal (VP) Shunt Infection caused by Enterobacter cloacae 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 12.4 145 10.1 273 4.3 29 0.71 38.4 CSF Fluid Analysis Color Colorless Appearance Clear RBC 11 WBC 67 Glucose 49 T. Protein 59 Glucose CSF/Serum Ratio: 0.46

Cefepime 2g IV q 8 + Vancomycin 1g IV q 12 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 Peak incidence in 6th/7th decade of life More common in females than males (2-3:1) 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 “Shunt” comes from the Middle English word shun which indicates being pushed away or “to the side” and suggests diversion. There is ~150mL of CSF in an average 70kg adult, with 1/4th located in the ventricles VP, VA, and VPl shunts VP shunts are the most commonly placed and most versatile shunts for long-term management of hydrocephalus. Ventricular Shunting Procedures. In: Youmans Neurological Surgery. 6th ed. 2011.

VP Shunts – Complications Intraventricular hemorrhage Obstruction Over drainage of CSF Infection Infection is one of the most serious and requires prompt management. Incidence ranges anywhere from 5-41% in the literature, although the true range is likely 4-17% 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 Other Etiologies Coagulase negative Staphylococci spp. Candida albicans Staphylococcus aureus 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 Antibiotic Dosing Coag-negative Staph. spp. & MRSA Vancomycin 15mg/kg every 8-12 hours Gram-negative Bacilli (including Pseudomonas spp.) Ceftazidine Cefepime Meropenem 2g every 8 hours With internal shunts, externalization of the drain followed by treatment shows the most success. If Coag-neg staph or P. acnes, treat for 7 days (unless cx’s positive, hten tx until cx’s neg x 10 days) If staph aureus or GN bacilli, 10 days after cx’s negative prior to new shunt placement 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 What would you do?

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 Actually was an AmpC beta lactamase, but had not been named that. Has been found in mycobacterium, enterobacter, e coli, shigella, acinetobacter, psudomonas, and Ochrobactrum anthropi (and more!) Chromosomal vs Plasmid Clin Microbio Rev. 2009;22(1):161-182.

Verigene® Antimicrob Agents Chemother. 2010;54(3):969-976. AmpC is a class C beta lactamase. Our Verigene test does NOT test for AmpC resistance but DOES test for other Beta Lactamases. A, C, and D utilize an active serine at their site of action whereas class b are metalloenzymes that use zinc. Oxa is a class D. Oxa-1 and -10 hydrolyze cloxacillin and oxacillin. Oxa-11 and -15 are Ext spectrum cephalosporinases. -23 and -48 are carbapenemases IMP and VIM and NDM are class B. These are Carbapenemeases CTX-M is a class A breakdes down ext spectrum cephs including CTX, Ceftaz, and Cefepime KPC is a lass A and breaks down carbapenems Antimicrob Agents Chemother. 2010;54(3):969-976.

AmpC β-lactamase Induction B-Lactam Antibiotic Inducer? Substrate? Penicillin, aminopenicillins, cefazolin Strong Good Cefotaxime, ceftriaxone, ceftazidime, cefepime Weak Poor Cefoxitin, Imipenem 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 Binding of BL to organism prevents synthesis of intracellular compounds that signal the breakdown of B-lactamase. This essentially permanently turns “on” the production switch. There is a disruption in biosynthesis of a checmical that competitively binds to AmpR which is a regulator gene for ampC. Without this inhibitor, AmpR continuously activates the trnascription of AmpC. 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. Circle = Imipenem Rest = weak (ceftriaxone i.e.) Amp + CTX + Vanc for meningitis SPACE/SPICE (indole positive protea which includes Morganella and providencia) Pseudo and acinetobacter can display similar resistance, but they both typically have a variety of resistance mechanisms. 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 β-lactamase Antibiotic use selectively allows depressed mutants to proliferate The most common mechanism of hyperproduction is a mutation in AmpD which is responsible for turning off Beta-lactamase production, although mutations in AmpR can occur. Clin Microbio Rev. 2009;22(1):161-182

Stable Derepression of AmpC Production This data was taken from a prospective observational sutdy of patients with Enterobacter bacteremia. In this study 3rd generation cephalosporsins were associated with multiresistant Enterobacter isolates more than other antibiotics. Interestingly, several patients developed resistance during therapy. Repeat cultures were drawn and Enterobacter was able to be identified with a varied resistance pattern. This accounted for 6% of the overall treatment group and 19% of the group treated with a 3rd gen ceph. 1 patient developed resistance to an AMG and no isolates to other BL’s including imipenem, piperacillin, ticarcillin, aztronam, and ticarcillin/clavulanate. 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 These isolates included 263 Enterobacter spp. Hilty Int J Antimicrob Agents. 2013;41:236-49. Int J Antimicrob Agents. 2012;40:297-305.

Cefepime and AmpC Antibiotic Responders Non-responders Ceftriaxone 4 (47.1%) 3 (42.9%) Cefepime 16 (88.9%) 2 (11.1%) Pip/Tazo 5 (71.4%) 2 (28.6%) Meropenem 11 (100%) 0 (0%) Ciprofloxacin 6 (100%) Total 43 (84.3%) 8 (15.7%) Retrospective chart review of 51 Enterobacter cloacae BSI’s from 2001 in Australia. This is the Abx started AFTER ID and susceptibility “…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 Kang Case report: Limaye AP 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 Additionally numerous case reports have domeonstrated seizure exacerbation with the concomitant use of CP and VPA (in both adults and children!) Ther Drug Monit. 2012;34:599-603

Carbapenems and Valproate Retrospective study of patients receiving carbapenem antibiotics and VPA from 2008-2010 Design Received VPA to control or prevent seizures Had VPA concentrations checked regularly Received a carbapenem antibiotic Inclusion Criteria Stopped VPA before receiving carbapenem antibiotics Use of drugs known to interact with VPA Exclusion Criteria Park et al Ther Drug Monit. 2012;34:599-603

Results Park et al 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 Cefepime 2g IV q 8 + Vancomycin 1g IV q 12 Empiric Therapy Day 3: E. cloacae positive culture Day 4 Day 17: E. cloacae positive culture Cefepime 2g IV q 8 + Vancomycin 1g IV q 12 Ceftriaxone 1g IV q 12 Cefepime 2g IV q 8 Meropenem 2g IV q 8

Ventriculoperitoneal (VP) Shunt Infection caused by Enterobacter cloacae Case Presentation – January 28th, 2015 Brian Skinner, PharmD PGY-1 Pharmacy Resident St. Vincent Indianapolis Hospital