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

2. 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

3. 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

4. Patient Case
12.4
145
10.1
273
38.4
CSF Fluid Analysis
Color
Colorless
Appearance
Clear
RBC 11
WBC 67
Glucose 49
T. Protein 59
Glucose CSF/Serum Ratio: 0.46

5. Cefepime 2g IV q 8 + Vancomycin 1g IV q 12
Clinical Course
Empiric Therapy
Cefepime 2g IV q 8 + Vancomycin 1g IV q 12

6. 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.

7. 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

8. 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

9. 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:
AACN Adv Crit Care. 2013;24(1)6-12.
CSF Shunt & Drain Infections. In: Principles & Practice of Infectious Disease. 8th ed

10. Empiric Treatment Options
Microorganism
Antibiotic
Dosing
Coag-negative Staph. spp. & MRSA
Vancomycin
15mg/kg every 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 ;362:
Clin Infect Dis. 2004;39:
AACN Adv Crit Care. 2013;24(1)6-12.

11. Susceptibility Data
What would you do?

12. 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 ;22(1):

13. 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 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 ;54(3):

14. 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 ;22(1):

15. 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 ;22(1):
Eur J Clin Microbiol ;6(4)

16. 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 ;22(1):

17. 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):

18. 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 ;41:
Int J Antimicrob Agents ;40:

19. 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 ;41:

20. 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 ;54:

21. 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:

22. Carbapenems and Valproate
Retrospective study of patients receiving carbapenem antibiotics and VPA from
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:

23. Results
Park et al
Ther Drug Monit. 2012;34:

24. 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

25. 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

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