Preventing C. difficile infection (CDI):

Everyone’s ResponsibilitySteven P. LaRosa, MD

Lahey Infectious Disease, Beverly

Disclosures/ Conflict of Interest• Scientific Advisory Board- ExThera Medical, Inc.- Seraph cartridge for

S. aureus bacteremia• Scientific Advisory Board- SciClone, Inc- Thymosin alpha for Severe

Sepsis• Associate Medical Director- New England LifeCare- Outpatient

Parenteral Antimicrobial Therapy• Clinical EndPoint Committee – Pfizer- Staph aureus vaccine study for

Orthopaedic Surgery• Data Safety Monitoring Board – Bristol Myers Squibb – anti-PDL-1 Ab

for Severe Sepsis

Disclaimer• “The findings and conclusions in this presentation are those of the speaker and do not necessarily represent the views of the entire Lahey Health System”

Clinical Vignette 1• 50 yo female with h/o ADHD, Anxiety and Remote cocaine use• Sees PCP 12/27/2016- cough, green sputum, 1 fever- prescribed Z pak• Follow-up 12/20/2016- dry cough, rhinorrhea , pharyngitis, bilateral ear

effusions- prescribed Amox/Clav 875mg po BID until 1/9/2017• Admitted to BH with nausea, vomiting, diarrhea 1/13/2017• 1/14/2017- pancolitis on CT, positive C diff toxin- placed on 500mg Vanco po

q6+ IV Tigecycline • 1/15/2017- severe sepsis with lactic acidosis and AKI• 1/15/2017- taken to OR for ex lap and loop ileostomy for installation of

Vanco “Pittsburgh Procedure”• 1/16/2017- Died

Case Vignette 2• 83 yo male with h/o C diff in past, GERD on PPI, CRI admitted

12/6/2017 for elective lumbar surgery• Received 24 hours (3 doses of Cefazolin q 8 hours )• 12/11/2017- developed nausea, vomiting and WBC count to 20,000• C diff toxin returns positive- started on po Vancomycin• Evolves into severe sepsis and dies 12/14/2017

Clostridium difficile Infection (CDI)• Leading Hospital-Acquired infection in the US• ~ 500,000 cases in the US/year• 29,000 deaths annually• 4.8 Billion dollars in excess medical costs• Recurrence rate with treatment 20-30%

• 1-3 additional hospitalizations• 19-24 additional hospital days• $11, 469-$12, 617 additional Medicare payments

• 5-15% of hospital admissions with asymptomatic carriage of toxigenic C. difficile

Lessa FC, et al. N Engl Jnl Med 2015;372(9):825-834.Zilberberg MD, et al. Medicine 2017;96:10

Choice of Antibiotic

Antibiotics associated with HIGH RISK of C. difficile

Cephalosporins: 2nd , 3rd and 4th generation (cefuroxime, ceftriaxone, cefepime)

Clindamycin Fluoroquinolones (ciprofloxacin,

levofloxacin)

Antibiotics associated with MEDIUM RISK of C. difficile

Beta-lactam beta-lactamase inhibitors (ampicillin/sulbactam, piperacillin/tazobactam)

Macrolides (azithromycin)

Antibiotics associated with LOW RISK of C. difficile

Aminoglycosides Carbapenems Cephalosporins: 1st generation Penicillin Semi-synthetic Penicillins (dicloxacillin,

oxacillin) Tetracyclines (doxycycline) Tigecycline TMP-SMX ( Bactrim) Vancomycin

*** No antibiotic is without risk

Avoiding High Risk Agents• An Antibiotic Stewardship program decreased Cephalosporin use by

33% and Fluoroquinolone use by 30% was associated with a 30% decrease in C Diff cases

Borde JP et al. Infection 2015;43-45-50

• Intervention to decrease use of high risk antibiotics ( 2nd and 3rd Gen Cephalosporins, fluoroquinolones)

• Significant change in usage of high risk antibiotics and a decrease in CDI incidence rate to 0.0047/110-bed days/ month (p=0.0081)

Aldeyab MA et al. J Antimicrob Chemother 2012;67:2998-2996

4C National Antibiotic Stewardship Intervention• Targeted inpatient and out patient use of high risk agents in Scotland

• Cipro/Fluoroquinolones• Co-amoxiclav• Clindamycin• Cephalosporins (3rd and 4th Generation)

• Amox or Cotrimoxazole encouraged in place of Quinolones and Co-amoxiclav• Pip-tazo encouraged in place of Ceftriaxone• A 50 % drop in 4C antibiotic usage was observed in the hospital and community• A reciprocal 50% increase in cotrimoxazole, amoxicillin, gentamicin and piperacillin-tazobactam

usage• C. diff infection prevalence fell by 68% in hospitals and 45% in the community

Lawes T et al. Lancet Infect Dis 2016; 17 (2):194-206

Risk of C diff colonization• Point-prevalence fecal culture surveys and fecal suspension inhibitory assays• Groups : Inhibitory antibiotics ( Pip-Tazo, ampicillin, amoxicillin, linezolid,

metronidazole, imipenem, meropenem, tetracycline, tigecycline) vs Non-inhibitory antibiotics (Cephalosporins, Cipro, Trimethoprim/sulfamethoxazole)

• 250 patients screened – 32 (13%) asymptomatic carriers• 1/36 , 3% carriers in Pip-Tazobactam vs 7/36, 19% in non-inhibitory group

(p=.0024)• Fecal suspension inhibitory to C diff: 20/28 vs 3/11, p=0.03)• Other inhibitory antibiotics did not prevent asymptomatic carriageDonskey CJ et al. BMC Infectious Diseases 2016;16:159

Adjusting Empiric Antimicrobial RegimenIndication Current Regimen Alternative

CAP Azithro+Ceftriaxone Azithro+ Amp/Sulbactam

HCAP/VAP/HAP Vanco + Cefepime Vanco+ Pip/Tazo

Complicated UTI Ceftriaxone Pip/Tazo

Intra-abdominal Infection Ceftriaxone + Metronidazole Pip/Tazo

Non-purulent Cellulitis Ceftriaxone Amp/Sulbactam or Cefazolin

Empiric Sepsis Vanco + Cefepime Vanco+ Pip/Tazo or Meropenem

Duration of Antibiotics: Shorter is Better

Duration of Surgical Antimicrobial Prophylaxis• Last HICPAC/CDC guidelines on surgical site infection 1999• Update should be out in press any time• Preview given by Dale Bratzler at ID WEEK 2016 on Oct 27,2016• In clean and clean-contaminated procedures, do not administer

additional prophylactic antimicrobial doses after the surgical incision is closed in the operating room, even in the presence of a drain

• Category 1A recommendation• Based upon 45 RCTs in cardiac, thoracic, vascular, ENT, gynecologic,

orthopaedic and general surgery

COPD/ AECB• Meta-analysis • 21 studies, 10,968 patients• Compared antibiotic treatment < or = 5 days vs > 5 days• Clinical Cure < 25 days – OR 0.99 ( 95% CI 0.90-1.10)• Late follow up -OR 1.0 (95% CI 0.91-1.10)

El Moussaoui R et al. Thorax 2008;63:415-422

CAP• RCT, 312 hospitalized patients• Control group vs Intervention Group• Intervention group – antibiotics stopped at 5 days if:

• Temp < 37.8C for 2 days a no more than 1 sign of clinical instability:• SBP < 90mmHg• HR> 100• RR>24• O2 sat < 90% or PaO2 < 60 Hg on room air

• Results:• Clinical success at Day 10: 50.4% in control vs 56.36% intervention (p=.18)• Clinical success at Day 30: 88.6% in control vs 91.9% intervention (p=.33)

Uranga A et al. JAMA Intern Med 2016;76(9):1257-1265

CAP• RCT, Netherlands• Inpatients, Moderate-Severe Pneumonia CAP (PSI 110 or less)• 3 days IV Amox , followed by 5 days of oral Amox 750mg or placebo

TID X 5 days if clinically improved• Placebo=56, Amox=64• Results:

• Clinical Cure –Day 10: (93% in both groups (0.1 (-9-10)• Clinical Cure –Day 28: 90% 3-day group vs 88% in 8 day group (2 (-9-15)

el Moussaoui R et al. BMJ 2006;332(7554):1355

Cellulitis• RCT of 87 subjects with cellulitis• At day #5 patients without:

• Clinical worsening• A persistent nidus of infection• a lack of any clinical improvement• An abscess

• Randomized to 5 days or Levofloxacin 500mg/day or placebo• Primary Infection was resolution of infection at Day #14• 98% success in both groups at Day #14 and Day #28Hepburn MJ et al. Arch Intern Med 2004;164:1669

Pyelonephritis/ Septic Urinary Tract• Meta-analysis of 8 RCTs• n=2515, 1239 treated for < or = 7days and 1276 treated for > 7 days• Endpoint is clinical failure at end of long treatment arm (10-14 days)• 37/549 (6.7%) short group vs 59/527 (11.2%) long group (RR

0.63[0.33-1.18])• Use of same antibiotic, Type of antibiotic, and presence or absence of

bacteremia did change results

Eliakim-Raz N et al. J Antimicrob Chemother 2013;68:2183-2191

Intra-abdominal Infection• RCT• 518 patients with complicated intraabdominal infection and adequate source control• Randomized to:

• Fixed course of 4 days antibiotics (experimental group)• 2 days after resolution of fever, leukocytosis and ileus with max of 10 days

(control group)• Combined Endpoint: surgical -site infection, recurrent intraabdominal infection or

death within 30 days of source control procedure• Results: 56/257 (21.8%) experimental group vs 58/260 (22.3%) control group( -0.5%,

95%CI( -7.0-8.0); p=0.92• Median duration of therapy: 4 days in experimental group vs 8 days in control groupSawyer RG et al. N Engl Jnl Med 2015;372:1996-2005.

Indication Duration of Antibiotic Therapy

Cystitis 3 days

Complicated UTI/pyelonephritis

≤ 7 days

Intra-abdominal Infection 4 days is sufficient if source control is achieved

HCAP/HAP/VAP 7 days

CAP 5-7 days

Cellulitis 5 days

Acute Exacerbation of COPD 5 days

Sinusitis ≤ 7 days

Shortening Duration of Therapy

Shortening Duration of Antibiotic Therapy• All empiric antibiotic therapy should be re-visited after 72 hours (ANTIBIOTIC TIME OUT):

• Consider clinical course• Microbiologic data• Evolution of biomarker data

• De-escalate antimicrobial therapy based on ID and sensitivity of cxs• Stop antibiotics if no evidence of infection

• Involves the Nursing Staff incorporating antibiotic use during daily patient rounds• Involves the Micro lab utilizing technology for rapid turnaround time• Involves IT making sure that BPAs and templates are present • Involves hospital leadership to make sure that IT and Micro have resources available

Biomarkers Could Help

PCT -BIOCHEMISTRY• PCT – 116 amino acid protein with sequence

identical to that of prohormone of calcitonin• Under normal conditions: procalcitonin

calcitonin in C-cells of thyroid gland• In severe bacterial infections and sepsis: intact

procalcitonin in blood synthesized and released from macrophages and monocytic cells of other organs, e.g. liver, neuroendocrine cells in the lung

PCT to guide ABX therapy in CAP

Christ-Crain et al, Lancet 2004Christ-Crain et al, Chest 2004, 126(4): 708S

In patients diagnosed with CAP, the

investigators could demonstrate a

reduction of the duration of

antibiotic courses from 12 to 5 days by

using PCT.

2. Procalcitonin-guided treatment reduced the duration of antibiotic treatment in CAP patients

Procalcitonin and Community Acquired Pneumonia

The Specific Issue of “UTIs”

Asymptomatic Bacteriuria (ASB)• Positive urine culture without any clinical signs of UTI• No evidence that treatment with antibiotics has clinical benefit• Recommendations are to treat ASB only in setting of pregnancy and

impending urologic instrumentation• 45-65% of patients with ASB receive inappropriate antibiotics

Diagnosis of UTI• Change in mental status or change in color or odor of urine are often

found in asymptomatic bacteriuria and respond to hydration• A urine culture and blood culture with the same organism suffices for

the diagnosis of UTI if there is no alternative source for the bacteremia

Diagnosis of UTI- no catheterAt least one of the following to send UA and start antibiotics :• Acute dysuria or pain in testes,

epididymis, prostate• Fever or leukocytosis and 1 of the

following:• Acute CVA pain/tenderness• Suprapubic pain• Gross hematuria• New or increase in incontinence• New or marked increase in urgency• New or marked increase in frequency

In the absence of fever or leukocytosis 2 of the following:

• Suprapubic pain• Gross hematuria• New or increase in incontinence• New or marked increase in

urgency• New or marked increase in

frequency

Stone ND. Infect Control Hosp Epidemiol 2012;33 (10):965-977

Diagnosis of UTI- catheterizedMust have 1 or below to send UA and start antibiotics:

Fever or rigors or new onset hypotension with no alternative explanation

New suprapubic or CVA pain or tenderness

New dramatic change in mental status or functional decline with no alternative diagnosis and leukocytosis

Purulent discharge around catheter or acute pain or swelling in testes, epididymis or prostate

Stone ND. Infect Control Hosp Epidemiol 2012;33 (10):965-977

The Patient with h/o past C diff or Fecal transplant

Approach to Patients with Prior C diff• Should be “flagged” in EMR as past C diff• No antibiotics unless absolutely necessary• Use of antibiotics with lower risk – Doxycycline, Bactrim, Tigecycline• Shortest duration possible• Oral Vancomycin prophylaxis (OVP)

“Gut-sparing” treatment of UTI• 19 patients with h/o fecal transplant or rCDI• Treated with 3 days of IM or IV Gentamicin ( 160mg Day #1, 80mg on

Day #2 and Day #3)• Resolution of UTI sx• No recurrent C diff• No significant change in microbial diversity of fecal microbiota

Staley C et al. J Antimicrob Chemother 2016

Oral Vanco Prophylaxis (OVP) to Prevent rCDI• Retrospective Study• Evaluable Population: Patients with h/o CDI admitted and received systemic antibiotics• Compared OVP group to control group• OVP group n=71 (125 mg twice daily, 250mg twice daily during antibiotics and for up

to 1 week after)• Control group n=132• Endpoint: recurrent CDI in 4 weeks after finishing antibiotics• Results:

• More patients in OVP group were on H2RA or PPIs• CDI in 3 (4.2%) in the OVP group vs 35 (26.6%) in control group (OR 0.12 ;95%CI

0.04-4) ; p< .001)Van Hise NW et al. Clin Infect Dis 2016;63 (5):651-653

Hand Hygiene: Soap and Water !

Hand Hygiene• RCT• Patients with CDI or asymptomatic carriage of toxigenic C diff

randomized to:• Alcohol hand rub• Soap and water with triclosan

• Comparison : Frequency of Hand Contamination and CFUs• Statistically significant Reduction in % of hands with positive cultures

and CFUs after hand washing with soap and water but not after alcohol rub

Donskey CJ et al. ICHE 2014

Probiotics

Meta-analysis of probiotics for the prevention of Clostridium difficile-associated diarrhea in adults or children, from Johnston et al [6].

Charlesnika T. Evans, and Stuart Johnson Clin Infect Dis. 2015;60:S122-S128

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Hot off the Press!• Meta-analysis• 19 studies, n=3277 probiotics, 2984 placebo• RR with probiotics 0.42 (95% CI:0.30-0.57; p<.001)• NNT is 43• RR 0.32 if probiotics started within 2 D of antibiotics vs 0.70 if started > 2 days

after antibiotics• Lactobacillus containing formulation RR 0.34 (95% CI:0.19-0.61)• Saccharomyces RR 0.63(95%CI:0.29- 1.37)

Shen NT et al. Gastroenterology (Accepted 3 FEB 2017)

Meta-analysis of randomized trials of probiotics for primary prevention of Clostridium difficile infection in adults by Johnson et al [3].

Charlesnika T. Evans, and Stuart Johnson Clin Infect Dis. 2015;60:S122-S128

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Bio K+RRR=71.2% (SS), NNT=16

FlorastorRRR 32.5% (NS)NNT=61

BIO K +• 2 caps (100 billion CFU/ day) beginning within 36 hours of antibiotic

start and continuing for 5 days after antibiotics• $4.20/day x 12 days on average X 16 patients to prevent 1 case of

CDAD= $806.40• Cost of 1 case of CDI = ~ $8000

* IT could associate antibiotic order with BIO-K order or fire an alert when antibiotics are ordered

Decreasing Proton Pump Inhibitors

PPI use and Infection Risk• Pneumonia:

• Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09-1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25-2.19), PPI high dose (OR: 1.50; 95% CI: 1.33-1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11-1.24) were significantly associated with CAP

Expert Rev Clin Pharmacol. 2012 May;5(3):337-44• 30% increase risk for HAP in patients receiving PPI for 3 daysJAMA. 2009 May 27;301(20):2120-8

• C diff:• Community acquired C. diff 2.9-3.5x increased risk

JAMA. 2005;294(23):2989

CMAJ. 2006;175(7):745.• Recurrent infection- 1.58-2.5X increased risk ICHE 2015;36 (4):452-460Journal of Hospital Infection 2008;70:298-304• Nosocomial acquisition- dose dependent increased risk 1.74-2.36 X Arch Intern Med. 2010;170(9):784.

Guidelines for use of PPI for UGI bleeding Prophylaxis in the hospital• Patients requiring mechanical ventilation• Intensive care patients with coagulopathy (INR >1.5, platelets <50K)• Patients with prior history of peptic ulcer disease, particularly those

receiving nonsteroidal anti-inflammatory drug or antiplatelet therapy

GI Indications for Starting/Continuing PPI• Patients admitted with hematemesis or melena• Gastric ulcer/duodenal ulcer/esophagitis on endoscopy• On H. pylori therapy• Complicated GERD

• Stricture• Barrett’s esophagus

• Patients with documented h/o GI bleeding in past

Stopping PPIs• Active C. diff infection

• Stop PPI until treatment complete and then reconsider indication for PPI

• Simple (non-complicated) GERD• Consider PRN PPI or H2 blocker

• Patients who do not know why they are on PPI, and deny dyspepsia• Stop PPI

Using the EMR• 3 phases:

1)Baseline2) CPOE alert when there is co-administration of PPI and antibiotic3) Alert + antimicrobial stewardshipResults:• No change in GI consults or transfusion rates• No change in CDI rates

• No

Time Period PPI+ABX(DOT/100pt days)

ABXDOT/100 pt days

PPIDOT /100 pt days

Baseline 4.99 18.98 33.52Alert 3.14 14.98 29.50Stewardship 1.80 8.90 23.95

p value in each column between all groups < 0.001Kandel CE et al. BMC Infectious Diseases 2016;16:355

Conclusions• Avoid high risk antibiotics (4 Cs)• Antibiotic duration should be as short as possible• Don’t order UA and start antibiotics for UTI unless there is some GU

symptom• Start BIO K+ probiotic in all patients at the same time as systemic

antibiotics• Gastric acid suppression only in those with an indication• Wash your hands! (with soap and water)• Patients with past C diff are a high risk population