URINARY TRACT INFECTION WITH ESBL PRODUCING E.

COLI
Jordan King, PharmD Candidate 6-28-2013

Learning Objectives
Review a patient with an ESBL producing UTI from admit

to discharge Understand the basic epidemiology and etiology of an UTI Review the current recommendations in the IDSA guidelines on UTIs Recognize the different types of ESBLs

PATIENT CASE

Patient Case: History of Present Illness

06/04/13 MC is a 84 y/o female with history of CKD, DM type II, and recurrent UTI. She presents to the ED with 5 days of worsening abdominal pain associated with some N/V. PO intake has been quite poor related to very little appetite. Patient has a history of increased frequency of urination which has worsened in the recent days. She notes chills and body aches, but denies any dysuria, fevers, or chest pain.

Patient Case
PMH
Diabetes Mellitus type II Hypertension Hyperlipidemia

Physical Exam
BP: 105/50 HR: 91 RR: 23

Chronic Kidney Disease

Renal Artery Stenting GERD Chronic urinary frequency

Temp: 36.4
O2 Sat: 92% on 3-4 L/min

Hx of UTI with Extended-

spectrum beta-lactamase (ESBL) producing E.coli

Patient Case
Labs
WBC: 36.8 Hgb: 14.0 Hct: 41.9 Plts: 311 BUN: 73 SCr: 3.03 (baseline 1.7)

Urinalysis
Appearance: Cloudy WBC: > 30 Bacteria: 4+ Leukocyte esterase: (+) Protein: 100 (2+) Nitrite: (-)

INR: 1.1
Lactate: 2.9

Patient Case: Assessment in ED

1. Severe sepsis

2. Recurrent UTI
3. Lactic acidosis 4. Acute on chronic kidney failure

URINARY TRACT INFECTIONS

Epidemiology of UTIs
Female > Male Exception is infants 50%-80% of women will develop an UTI during their life 20%-30% of these women will develop a second UTI The majority of men who develop an UTI have a

functional or anatomical abnormality

One of the most common reasons for antibiotic Rx

Common Organisms
Uncomplicated Cystitis and Pyelonephritis
Bacteria usually originate from bowel flora of host

Escherichia coli (75%-95%) Staphylococcus saprophyticus Proteus mirabilis Klebsiella pneumoniae

Common Organisms in Complicated UTI

Risk Factors
Female Obstruction Inhibit normal flow of urine Incomplete emptying; urinary reflux Neurologic malfunctions Incomplete emptying Urinary catheterization Mechanical

instrumentation
Use of

spermicides/diaphragms
Pregnancy

Recent sexual intercourse

Post-Transplantation Risk of Urinary Tract Infection in Renal Allograft Recipients with Ureteral Stents
Methods: Retrospective chart review of incidence of UTI in all renal allograft recipients transplanted between January 2007 and March 2009 at one institution. Recipients were categorized as non stent group or stent group Results: Primary endpoint - Overall incidence of UTI within 1 year posttransplantation was similar between the two groups (22.5% vs 19%, p=0.38) Conclusion: Ureteral stents are not associated with increased risk of post-transplant UTI

Urinary Tract Infections

Signs and Symptoms
Cystitis Dysuria, urinary frequency, urinary urgency, nocturia, suprapubic discomfort Pyelonephritis Fever, nausea, vomiting, flank pain, and malaise

Other non-specific signs of infection

Complicated vs Uncomplicated
Uncomplicated UTI: refers to acute cystitis or pyelonephritis in nonpregnant outpatient women without anatomic abnormalities or instrumentation of the urinary tract

Complicated UTI: catch-all term that encompasses all other types of UTI

Complicated UTIs
Age (children or >60) Anatomic/functional Male Inappropriate

abnormality
Foreign body Immunosuppressed

antibiotics/resistance
Obstruction Pregnancy

Complicated UTIs
Diabetes Pregnancy Hx of pyelonephritis in past year Hx of UTI in childhood S/S for >7 days before seeking care Broad-spectrum antimicrobial Indwelling urethral catheter, stent,

or nephrostomy tube
Functional or anatomical

abnormality of the urinary tract

Urinary tract obstruction Renal transplant Immunosuppression

resistant pathogen
Hospital acquired

Organism Resistance
IMC Antibiogram

IDSA GUIDELINES
Urinary Tract Infections

Treatment of Uncomplicated Cystitis

Nitrofurantoin 100mg PO BID x5days Avoid if pyelonephritis suspected C/I if CrCl <60ml/min Trimethoprim-Sulfamethoxazole 160-800mg PO BID

x3days
Avoid if resistance is known to exceed 20%

Fosfomycin 3gm PO x1 Avoid if pyelonephritis suspected Lower efficacy than some other recommended agents

Treatment of Uncomplicated Cystitis

Alternatives
Ciprofloxacin, levofloxacin (3 day regimen) Should be reserved for important uses other than acute cystitis Amoxicillin/Clavulanate, cefdinir, cefpodoxime (3-7 day

regimens)
Generally have inferior efficacy and more adverse effects

Should be used with caution for uncomplicated cystitis

Amoxicillin, Ampicillin should NOT be used for empirical tx

Treatment of Uncomplicated Pyelonephritis in Patients NOT requiring hospitalization

Ciprofloxacin 500mg PO BID x7 days (+/- 400mg IV initial)

Ciprofloxacin ER 1000mg PO QD x7 days

Levofloxacin 750mg PO QD x5 days If resistance to community pathogens >10%, an initial 1x IV dose of 1gm Ceftriaxone or consolidated 24-h dose of an aminoglycoside If CrCl <50mL/min adjust dose Trimethoprim/Sulfamethoxazole 160/800 PO BID x14 days If susceptibility is unknown, an initial 1x IV dose of 1gm Ceftriaxone or consolidated 24-h dose of an aminoglycoside Oral -lactams Less effective than other options if used, an initial 1x IV dose of 1gm Ceftriaxone or consolidated 24-h dose of an aminoglycoside

Treatment of Uncomplicated Pyelonephritis in Patients requiring hospitalization

Initially treat with IV antibiotics flouroquinolones aminoglycosides (+/- ampicillin) extended-spectrum cephalosporins extended-spectrum penicillins (+/- aminoglycosides) carbapenems

Prevention
Systemic antimicrobial prophylaxis should not be routinely

used Methenamine salts should not be routinely used Cranberry products should not be routinely used Catheter irrigation with antimicrobials should not be used routinely Antimicrobial or antiseptics should not be routinely added to the drainage bag Prophylactic antimicrobials, given systemically or by bladder irrigation, should not be routinely administered at the time of catheter placement

Duration of Treatment
Prompt resolution of symptoms 7 days Delayed response 10-14 days Patients who are not severly ill 5 day levofloxacin Women <65 y/o without upper UTI symptoms 3 days

Recommended medications
Data on local antimicrobial resistance, when available,

should be used to help guide empirical treatment. Shorter durations of treatment are preferred in appropriate patients to limit development of resistance.

Limited specific drug recommendations Levofloxacin 750mg PO or IV QD x5 days (not severely ill)

ANTIMICROBIAL RESISTANCE

Early Resistance
First -lactamase was identified in E. coli before penicillin

was used in medical practice

Many gram (-) bacteria have a naturally occurring -

lactamase
Thought to have developed from -lactam producing soil

organisms

E. Coli mechanism of resistance

-lactamases Resistance to aminopenicillins and narrow spectrum cephalosporins ESBL Resistance to third generation cephalosporins and monobactams
ESBLs are defined as -lactamases capable of hydrolyzing

oximino-cephalosporins that are inhibited by clavulanic acid

Cefotaxime, ceftriaxone, ceftazidime

Susceptible against cephamycins

Cefoxitin, cefotetan

ESBL
Over 150 different ESBLs have been identified TEM, SHV, CTX-M, OXA, IRT Not all strains are ESBLs Plasmid-mediated; Point mutations ESBL subtypes are not as efficient as parent enzymes at

hydrolyzing penicillins
activity against expanded-spectrum cephalosporins
susceptibility to -lactamase inhibitors (clavulanic acid)

TEM
Most commonly encountered -lactamase in gram (-)

Responsible for up to 90% of ampicillin resistance in E.

coli Most often found in E. coli and K. pneuomniae

SHV
Most commonly found in K. pneumoniae Relatively few derivatives of SHV compared with TEM Majority possess the ESBL phenotype

CTX-M
New family of ESBLs

Mainly found in Salmonella enterica and E. coli

Probably derived from AmpC, not SHV or TEM Greater activity against cefotaxime than ceftazidime

OXA
Charicterized by their high activity against oxacillin Poorly inhibited by clavulanic acid Mainly found in P. aeruginosa High resistance in P. aeruginosa; weak resistance in E. coli

Inhibitor-Resistant -Lactamases (IRT)

Not technically an ESBL

Dervived from TEM or SHV

Mainly found in E. coli Resistant to inhibition by clavulanic acid (and sulbactam) Susceptible to inhibition by tazobactam Mutant strains have been found in the lab that possess

ESBL and IRT phenotypes

Resistant to clavulanic acid and resistant to expanded-spectrum

cephalosporins

Treatment
Carbapenems May be susceptible to cefepime Only recommended in the NOT severly ill because of risk or resistance from other mechanisms Theoretically resistant to anything combined with

clavulanic acid
Not clinically significant

PATIENT CASE

Patient Case
Emergency Department 1. Urosepsis
Piperacillin/tazobactam 3.375mg IV Levofloxacin 750mg IV Imipenem/Cilastin 500mg IV

0.9% NS 2L

2. Pain Fentanyl IV 3. Nausea/Vommitting Ondansetron IV

Patient was admitted to the medicine floor

Patient Case
6/5/13 D/C all antibiotics received in ED Start meropenem 500mg IV Q12H
Renal dose

14 day antibiotic course

Continue fluid for acute kidney injury

Culture Results
06/04/13 (updated 06/06/13) Urine Culture
>100000 CFU/mL Escherichia coli ESBL producer S: imipenem, meropenem, nitrofurantoin R: amox/clavulanic acid, ampicillin/sulbactam, ampicillin, aztreonam, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, cephalothin, ciprofloxacin, gentamicin, levofloxacin, piperacillin/tazobactam, tobramycin, trimeth/sulfa, piperacillin, ticar/clavulanic acid, cefpodoxime

Blood Culture
No Growth 5 days

Patient Case
6/6/13 Continue Meropenem for recurrent UTI (day 3/14) Kidney function worsened
Change dose to 500mg IV Q24H

Considered need for prophylactic antibiotic with Macrobid Renal ultrasound negative for hydronephrosis

Labs: CO2: 12 () Anion Gap: 18 () SCr: 3.4 () BUN: 85 () WBC: 31.2 () H/H: 11.6/35.1 ()

Patient transferred to the STICU

Patient Case
6/8/13 Patient returns to the medicine floor
On ventilator and PICC placed in STICU

Renal function has improved Altered mental status resolved

Continue meropenem (day 5/14)

Sepsis improving

6/9/13 Sepsis has resolved Continue meropenem (day 6/14) Renal function continues to improve
Discuss changing back to meropenem 500mg IV Q12H

Patient Case
6/10/13 Change meropenem to ertapenem 500mg IV Q24H Patient continues to improve clinically Discharge scheduled

6/11/13 Patient discharged to a SNF

References

Gupta K, Trautner BW. Chapter 288. Urinary Tract Infections, Pyelonephritis, and Prostatitis. In: Fauci AS, Kasper DL, Jameson JL, Longo DL, Hauser SL, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGrawHill; 2012. http://nv-ezproxy.roseman.edu:2062/content.aspx?aID=9131197. Accessed June 25, 2013. Bradford, PA. Extended-Spectrum B-lactamases in the 21st century: Charicterization, Epidemiology, and Detection of This Important Resistance Threat. Clin Microbiol Rev. 2001 Oct;14(4):933-51. Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician. 2005 Mar 1;71(5):933-42. Coyle EA, Prince RA. Chapter 125. Urinary Tract Infections and Prostatitis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://nv-ezproxy.roseman.edu:2062/content.aspx?aID=8004270. Accessed June 27, 2013. Tenover FC. Mechanisms of Antimicrobial Resistance in Bacteria. Am J Med. 2006 Jun;119(6 Suppl 1):S3-10. Zhang SX, Parisian F, Yau Y, et al. Narrow-Spectrum Cephalosporin Susceptibility Testing of Escherichia coli with the BD Phoenix Automated System: Questionable Utility of Cephalothin as a Predictor of Cephalexin Susceptibility. J Clin Microbiol. 2007 November; 45(11): 37623763. Jacoby GA, Munoz-Price LS. The New B-Lactamases. N Engl J Med 2005; 352:380-391 Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Disease Society of America. Clin Infect Dis. 2010 Nov;50:625-63. Gupta K, Hooton TM, Naber KG, et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120.