Optimizing Antibiotic Use in the ICU

A Practical Approach to Antimicrobial Stewardship

George Sakoulas, MDUCSD School of Medicine

Sharp Memorial Hospital, San Diego, CA

July 2013

Some Points to Consider• The antibiotic era is 4.5 billion years old• Resistance to antibiotics exists in nature before

medicine actually discovers or uses them• Unlike any other class of medication, antibiotics

treat not only the individual, but have societal impacts

• 70% of antibiotics in USA go toAnimal Husbandry

Antimicrobial Treatment Considerations

• Must be timely: delay in initiation potentially lethal

• Appropriate: must cover the offending pathogen(s)

• Administered at adequate dose and intervals consistent with pK/pD parameters

• Timely streamlining based on clinical response and microbiological data

• Prompt discontinuation when practical

Deresinski S. Clin Infect Dis 2007; 45:S177-S183Allerberger F et al. Clin Microbiol Infect 2008; 14: 197-199.

Adapted from Kollef MH et al. Chest. 1999;115:462-474.ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

“…selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.”

– ATS/IDSA Guidelines

A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality

Inadequate antimicrobial treatment(n=169)

Adequate antimicrobial treatment(n=486)

0

10

20

30

40

50

60

All-Cause Mortality Infection-Related Mortality

24

42*

18

Hos

pita

l Mor

talit

y (%

)

52* *P<.001

Importance of Initial, Appropriate Antibiotic Therapy

ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America.

Discovery of New Antibiotic Classes

Novel Antibiotic Development

Geographic Distribution of KPC Producers in USA

ESKAPE and Mortality in Bacteremia

• VRE (n=683) vs VSE (n=931) OR 2.52 (1.9-3.4) Ref 1• MRSA (n=382) vs MSSA (n=433) 11.8% vs 5.1% (p< 0.001) Ref 2• Klebsiella pneumoniae 52% vs. 29% (p=0.007) Ref 3

– ESBL (n=48) vs non-ESBL (n=99)

• Acinetobacter baumanii 58% vs. 28% (p< 0.05) Ref 4– Imipenam R (n=40) vs S (n=40)

• Pseudomonas aeruginosa 21% vs. 12% (p=0.08) Ref 5– MDR (n=82) vs non-MDR (n=82)

REFERENCES1. Diaz-Granados et al. Clin Infect Dis 2005;41: 327-333.2. Melzer M et al. Clin Infect Dis 2003; 37: 1453-1460.3. Tumbarello M et al. Antimicrob Agents Chemother 2006; 50: 498-504.4. Kwon K et al. J Antimicrob Chemother 2007; 59: 525-530.5. Aloush V et al. Antimicrob Agents Chemother 2006; 50: 43-48.

Clostridium Dificile

• Poor Hand Hygiene– Mechanical scrub with soap and water

• Poor Environmental Cleanliness• Indiscriminate use of antibiotics

What is Antimicrobial Stewardship?

• Systematic approach to optimize clinical outcomes while minimizing consequence of antibiotic use– Toxicity– Selection of resistance– Selection of virulent organisms– Clostridium dificile

• Combine with comprehensive infection control to limit emergence and transmission of resistance

• Reduce healthcare costs without adversely impacting care

• Bottom line-STREAMLINE therapy

Dellit T et al. Clin Infect Dis 2007; 44: 159-177

Stewardship Strategies in thePrescribing Workflow

California SB 739-HAI Initiative

Control and report healthcare-acquired infections (eg. Central line insertion practice)

Antibiotic stewardship included

“By January 1, 2008, [CDPH] shall take all of the following actions to protect against health care associated infections (HAI) in general acute care hospitals statewide:

Require that general acute care hospitals develop a process for evaluating the judicious use of antibiotics, the results of which shall be monitored jointly by appropriate representatives and committees involved in quality improvement activities.”

Economic Considerations for Antibiotic Stewardship

• Antibiotic use restriction and costs should not be the only focus

• Antibiotic costs are a small percentage of treatment costs

• Costs from hospital length of stay, total hospital costs, and infection prevention should be considered

• Return to productivity

General Antimicrobial Prescribing Principles

• Day 1: Empiric Antibiotics– Need rapid diagnotics– Mixing vs. Cycling

• Day 3: DE-ESCALATION– What antibiotics are being prescribed?– What do the cultures show?– Is there infection?

• LEUKOCYTOSIS = INFECTION• Fever is not necessarily due to infection

– What is the clinical picture?

DE-ESCALATIONDISCONTINUATION

STOP WHEN YOU ARE DONE!!

Kaplan-Meier Estimates of the Probability of Survival Probability of survival is for the 60 days after ventilator-assisted pneumonia onset as a function of the duration of antibiotics

Chastre, J. et al. JAMA 2003;290:2588-2598

No excess mortalityNo more recurrent infectionsMore antibiotic-free days

Antibiotic “Sink”The “UTI”

• UTI requires at least 1 of the following– Pyuria (>10 WBC/hpf)– Symptoms (dysuria, hematuria, urgency)

• BACTERIURIA IS NOT A UTI• QUANTITATIVE BACTERIURIA (CFU/ML) IS IRRELEVANT• The Only Patients in whom bacteriuria requires therapy

– Pregnancy– Renal transplant patients– Pre-op Patient

GENERAL UTI SUMMARY

• No need to treat– Nitrites– Bacteriuria other than pregnancy, transplant

• Treat UTI-> 3 days• Pyelonephritis -> 2 weeks

Biomarker: Procalcitonin (PCT)• 116 amino acid peptide, MW 13 kD; product of CALC-I gene• PCT is normally produced, enzymatically processed into calcitonin,

and stored in granules in the neuroendocrine C cells of the thyroid– Serum concentrations of PCT < 0.5 ng/mL

• Under condition of infection, PCT is produced constitutively by all cells– Direct toxins or LPS– Indirect stimualtion by pro-inflammatory cytokines: IL-, IL-6, TNF-– Serum concentrations up to 2000X increase

• First described to be elevated in staphylococcal TSS in 1983• Subsequently considered a potential parameter of infection in 1993

PCT Kinetics• Procalcitonin (PCT) increases after 2-3 hours after

induction e.g. by endotoxin • May increase to levels up to several hundred nanogram

per ml in severe sepsis and septic shock. • After successful treatment intervention the

procalcitonin value decreases, indicating a positive prognosis

• Persistingly high or even further increasing levels are indicators for poor prognosis.

• Levels then rise rapidly, reaching a plateau after 6-12 hours.

• PCT concentrations remain high for up to 48 hours, falling to their baseline values within the following 2 days. The half-life is about 20 to 24 hours.

Brunkhorst F.M. et al., Intens Care Med 1998, 24: 888-892

PCT Concentration Spectrum

Duration of Antibiotics for CAP

Christ-Crain M et al. Am J Respir Crit Care Med. 2006 Apr 7; Christ-Crain M & Müller B, Swiss Med Wkly 2005, 135: 451-460

Christ-Crain M et al. Am J Resp Crit Care Med 2006; 174: 84-93

Outcomes: Procalcitonin in CAP

PCT and Sepsis:Less Antibiotics, No Impact on Survival

Bouadma L et al. Lancet 2010; 375: 463-474

PCT DOES NOT Replace Routine Microbiology Or Clinical Judgment

• PCT may not elevated in some bloodstream infections

• S. aureus bacteremia• Enterococcus bacteremia• Subacute bacterial endocarditis• Candidemia

Where Else Are Molecular Rapid Diagnostics Needed and Used?

• Screening for resistant pathogens• RAPID Organism identification in sterile body

fluids– Fastidious organisms– Prior antibiotics negate cultures

• RAPID Susceptibility report• Risk Stratification of Patients

– More expensive more potent antibiotics perhaps for the sicker patients

Antibiotic Stewardship Must Coincide with Infection Control/Prevention

• Prevention– Optimal management of vascular and urinary

catheters– Prevention of LRTI

• Control– Hand hygiene– Contact precautions– Active surveillance– Education– Environmental cleaning– Improved communication between facilities

www.cdc.gov

Mindset of MD’s: What Influences Antibiotic Prescribing?

Conclusions• Physicians needs better tools on how to initiate and stop antibiotics

– Diagnostics– Education– Support systems

• Stewardship teams are just one step to regulate antibiotic prescribing

• The attitude of prescribing antimicrobials must switch from one of a right to one of a privilege

• Erase the “potential benefit>> potential harm” mindset of prescribing antibiotics

• De-escalate to narrower agents ASAP• Cut duration of antibiotics

• Early stop for non-infections• Short high dose course in cases of infection