Antibiotics:A rational approach in the ICU

The war against infectious diseaseshas been won.”

– Dr. William Stuart, U.S. Surgeon General,1969

In 1969……

Sobering Thoughts

•The pipeline is drying up! US FDA approval of new antibacterials down

56% from 1983 to 2002• Infectious diseases are still the most common

cause of death worldwide.• We are effectively living in the post-antibiotic

era• Therefore, we must manage carefully and

responsibly what we have

What Is Initial “Inadequate Therapy”?

Initial “Inadequate Therapy” In Critically Ill Patients with Serious

Infections Myth• There is time to start with one therapy and then

escalate later, if needed. Fact • Inadequate initial antimicrobial therapy increases mortality.

• Changing from inadequate to appropriate therapy may not decrease mortality.

• Initially delayed appropriate antibiotic therapy (IDAAT) is inadequate therapy.

Kollef MH et al. Chest 1999;115:462-474.Ibrahim EH et al. Chest 2000;118:146-155.Iregui M et al. Chest 2002;122:262-268.

Defining Initial Inadequate Therapy

• The antibiotic did not cover the infecting pathogen(s)

• The pathogen was resistant to the antibiotic

• Dosing was not adequate

• Combination therapy was not used, if indicated.

1Kollef MH et al. Chest 1999;115:462-474.2Ibrahim EH et al. Chest 2000;118:146-155.

Initial therapy is considered to be inadequate if:

Inappropriate Antimicrobial Therapy: Prevalence Among ICU

Patients

Source: Kollef M, et al: Chest 1999;115:462-74

Community-acquired infection

Hospital-acquired infection

Hospital-acquired infection after initial community-acquired infection

Inappropriate Antimicrobial Therapy (n = 655 ICU patients with infection)

Patient Group

Per

cent

Ina

ppr o

pria

te

Does Inadequate Therapy Result from Antibiotic Resistance?

• Inadequate therapy is more likely if antibiotic resistance is present, and antibiotic resistant organisms are more commonly associated with inadequate therapy (adapted from Kollef).

% Inadequate Treatment of VAP

Common

VAP

Sepsis Meningitis

Diabetic foot infections

Tackling Infections Easily?The Pure and Simple Truth?

• The truth is rarely pure and never simple.• So it is with tackling infections!

Sepsis: lethal and costly

Sepsis: lethal and costly• Annual incidence: ~750,000 cases in US• 2.26 cases per 100 hospital discharges• 51.1% received ICU care and 17.3% received

IMC care• Incidence and mortality increased with age• Case fatality rate: 28% • Economic burden– $22,100 per case– ~$16.7 billion nationally

Angus DC et al. 2001. Crit Care Med 29:1303-1310.

Sepsis: a common disease

• Incidence in US (cases per 100,000)– AIDS1 17– Colon and rectal cancer2 48– Breast cancer2112– Congestive heart failure3 ~196– Severe sepsis4~300

• Number of deaths in US each year– Acute myocardial infarction5 218,000– Severe sepsis4 215,000

1Centers for Disease Control and Prevention. 2000. Incidence rate for 1999. 2American Cancer Society. 2001. Incidence rate for 1993-1997.

4Angus DC et al. 2001. Crit Care Med 29:1303-1310. 5National Center for Health Statistics. 2001.

…becoming commoner• Incidence projected to rise during the next decade

– Aging population especially in developed nations

– Increased awareness and diagnosis– Immunocompromised patients e.g.

cancer therapy, transplantation)– Invasive procedures (ventilators, catheters,

prostheses)– Resistant pathogens

Angus DC et al. 2001. Crit Care Med 29:1303-1310.

Balk RA. 2000. Crit Care Clin 16(2):179-191

The light sat the end of the tunnel?

Mortality from Sepsis

Martin NEJM 2003

Most Effective Therapies“Early Goal Directed Therapy”

• Early recognition• of preshock: tachypnea respiratory alkalosis ( Paco2, pH >7.45)

• Fluid resuscitation• Antibiotics

• Effective• Early

• Drotrecogin α• ? Steroids in “non-responders”

Therapeutic interventions in Severe Sepsis: Effect on Mortality

Variable Odds Ratio 95% CI P value

Broad spectrum antibiotics0 - 1 hour 0.67 0.50-0.90 0.008

1 -3 hours 0.80 0.60 – 1.06 0.127

3 – 6 hours 0.87 0.62 – 1.22 0.419

Previous antibiotic 0.89 0.69 - 1.15 0.383

No antibiotic in 1st 6 hours 1

Fluid challenge (hypotension/ lactate > 36 mg%) 1.01 0.73 - 1.39 0.966

Low dose steroids in spite of above 1.04 0.85 – 1.28 0.688

Drotrecogin alfa in MOF 0.59 0.41 – 0.84 0.004

Effectiveness of Treatments for Severe SepsisFerrer R, Artigas A, Suarez D et al

AJRCCM 180:861-866, 2009

So, let’s concentrate on the antibiotics

Ibrahim Chest 2000

Blood Stream Infections: Adequacy of Antibiotics

Effect of Appropriate Antibiotics on Survival

Velles; Chest 2003

Velles; Chest 2003

Survival depends on severity of illness and appropriate empiric antibiotics

Each hour of delay increased mortality by 7.6% in the first 6 hoursAnand et al. Crit.Care Med 2006 (2150 patients)

Antibiotic treatment No. of patients who died/total no. of patients (%)

Empiric treatment Definitive treatment

Inappropriate treatment 228/670 (34%) 52/205 (25%)

Appropriate treatment

Beta lactam 131/789 (17%) 109/816 (13%)

Aminoglycoside 59/249 (24%) 44/193 (23%)

Beta lactam + aminoglycoside 62/327 (23%) 67/442 (15%)

Others

41/222

26/89 (29) 41/222 (18%)

Mortality and Antibiotic therapy- univariate analysis

Monotherapy vs.combination for gram neg. bacteremia--2124 patientsLeibovici et al. AAC 2004

Major Risk factors for mortality other than antibiotic treatment (in patients with gram-negative bacteremiaa

(Leibovici 1997)

Risk factor Survivors (1,652) Non-survivors(513)

Age (yr)b 60 74

Underlying disorder (% of patients)Steroid treatment 12.1

21.6Neutropenia 8.6

14.1Overt malignancy 20.9

32.0Hospital infection (% patients) 33.4

54.8

Unknown bacteremia (% patients) 16.8 33.7Pseudomonas sp. (% of patients) 13.9 22.0

Septic shock (% of patients) 3.2 32.8

a All comparisons are statistically significant (P # 0.0001).b Values are medians.

Nosocomial fungal pathogens

Systemic fungal infections

• Very important causes of mortality in ICUs

• Significant mortality – 50% in invasive aspergillosis

• 10% infections in ICUs attributable to fungal infections

• Candida is the commonest of all fungi followed by

Aspergilla

Risk factors for candidemia

Patients at risk of infection

Invasive candidiasis

Invasive aspergillosis

What Constitutes Initial Appropriate Therapy?

• Empiric broad-spectrum therapy initiated at the first suspicion of serious infection.

• Selection of antibiotic to ensure adequate coverage of all likely pathogens.

• Factors to consider when defining appropriate therapy:• Microbiologic data• Monotherapy vs. combination therapy• Dose and dosing frequency• Penetration• Timing• Toxicity• Risk of influencing resistance• Prior antibiotic use

Initial Appropriate Therapy

Kollef MH et al. Chest 1999;115:462-474.

The antibacterial therapy puzzle

Is the infection community-acquired or hospital-acquired?

Has the patient been treated with antibiotic recently?

Are there any risk factors for development of resistance/ poor outcome?

Factors in Selecting Initial Appropriate Therapy

• Patient features: Choose empiric therapy based on site and severity of infection, and physician assessment of the likelihood for deterioration and mortality.

• Local susceptibility and epidemiology: Choose empiric therapy to cover the likely infecting pathogens based on patterns while considering prior antibiotic therapy.

• Initial antibiotic therapy dosing and duration: Choose initial empiric therapy that will deliver enough antibiotic to the site of infection and be well-tolerated (consider antibiotic penetration).

• Combination vs. monotherapy: Initial antibiotic choice should give broad enough coverage, avoid emergence of resistance, and have the potential for synergy if necessary.

Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539.

Optimizing Combination Therapy in Critically Ill Patients Using Local Susceptibility Data

Optimizing Combination Therapy in Critically Ill Patients Using Local Susceptibility Data

All patients were ventilated > 7 days, and had received prior antibiotic therapy.

0 50 60 70 80

Aztreonam+ amikacin+ vancomycin

Piperacillin-tazobactam + amikacin + vancomycin

Ceftazidime + amikacin+ vancomycin

Imipenem + amikacin+ vancomycin

% susceptibility90 100

Timing

Importance of Timing of Antibiotic Administration

• 107 patients with VAP in a medical ICU• All patients received an antibiotic shown to be active

in vitro against the bacteria

– 33 patients received treatment that was delayed for 24 hours (28.6 5.8 hours) (classified as receiving IDAAT)

– 74 patients received treatment timely within 24 hours(12.5 4.2 hours)

• Risk factors for hospital mortality. Chest 2002;122:262–268

Appropriate Early Antibiotic Therapy Reduces Mortality Rates In Patients With Suspected VAP

Iregui et al. Chest 2002;122:262–268

Mortality (%)

Hospital mortality Mortality attributedto VAP

0

60

80

20

40

p<0.01

p<0.001

Initially delayed antibiotic treatment

Early appropriateantibiotic treatment

• All appropriate microbial specimens, including blood cultures , should be obtained before commencement of antibiotic therapy

• Blood cultures should be taken from a venepuncture site, after adequate skin antisepsis, and not from intravenous and intraarterial catheters

Basic Principles of Antibiotic therapy

• Once a decision is made to use antibiotics, they should be administered without delay.

• Broad spectrum empiric therapy at the outset• De-escalate: Start broad, go narrow • Use a narrow spectrum effective antibiotic when

the organism is identified• Monotherapy – effective against the expected

organisms aims to decrease drug toxicity, antagonisms.

Basic Principles of Antibiotic therapy

• Consider •the spectrum of the antibiotic’s action•pharmacokinetics and pharmacodynamics

• Where available• consult the infectious disease specialists• use additional tests such as MIC, antibiotic assay, serum bactericidal activity, synergy tests of antibiotic combination in serious infection

Antibiotic Pharmacology and the Antibiotic Pharmacology and the Pharmacodynamics of Bacterial KillingPharmacodynamics of Bacterial Killing

Pharmacodynamic ParametersIn Vivo Potency

T>MIC

Cmax:MIC

AUC:MIC

Concentration

Time

MIC

0PAE

Pharmacodynamic ParametersPredection of outcome

Parameter correlating with efficacy Cmax:MIC AUC:MIC T>MIC

Antibiotic Aminoglycosides Azithromycin

Fluroquinolones

Ketolides

Linezolid

Daptomycin

Tigecycline

Carbapenems

Cephalosporins

Macrolides

Penicillins

Organism killing Concentration-dependent

Concentration-dependent

Time-dependent

Therapeutic goal Maximize exposure

Maximize exposure

Optimize duration exposure

2 gm IV of Cefoperazone results in higher Cmax

Drugs 1981;22 (Suppl 1):35-45

1 gm as 3hr infusion1 gm as 3hr infusion 2 gm as 3hr infusion2 gm as 3hr infusion

3 hr infusion of 2 g Meropenem can achieve bactericidal exposures for pathogens that are considered to be resistant to meropenem

T> MIC : 60% of dosing interval

Clin Ther 2004; 26(8):1187-1197

Antimicrob Agents Chemother 2005;49(4): 1337-1339

Prolonged Infusion of Meropenem: Associated with Lower mortality

Superior life-saving effect of Meropenem in the 4h-group was mainly due to prolongation of the time above MIC realized by the prolonged infusion regimen.

Jpn J Antibiot. 2007 Jun;60(3):161-70.

Basic Principles of Antibiotic therapy

The general signs of infections are signs of systemic inflammation.Although bacterial infection is likely, consider non-infective causes of inflammation – especially when

appropriate antibiotics seem to failthere is a discrepancy between the overall clinical picture and the fever

Basic Principles of Antibiotic therapy

• Adequate doses should be given• IV route is preferable in critically ill patients, but

other routes should be considered when appropriate.

• Serum levels of antibiotics should be monitored, especially if hepatic or renal dysfunction is present,

• Prophylactic use of antibiotics should – be limited to certain situation– cover organisms that can potentially cause infections

in that specific group of patients,

Basic Principles of Antibiotic therapy

• The general signs of infections are signs of systemic inflammation.

• Although bacterial infection is likely, consider non-infective causes of inflammation – especially when– appropriate antibiotics seem to fail– there is a discrepancy between the overall

clinical picture and the fever

Use of Biomarkers for prognosis and diagnosis

Which Patients Are Candidates For

Initial Aggressive Antibiotic Therapy?

Patients Who May Benefit From Empirical Broad-Spectrum Antimicrobial Therapy

Critically ill patients with serious infections:

• Hospital-acquired pneumonia (HAP)• Ventilator-associated pneumonia (VAP)• Bacteremia• Severe sepsis

• Severe community-acquired pneumonia• Meningitis

What are the Principles in Choosing the Initial

Appropriate Empiric Therapy?Stage 1

Stage 1 • Administering the broadest-spectrum antibiotic

therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay)

Stage 2• Focusing on de-escalating as a means to minimize

resistance and improve cost-effectiveness

DE-ESCALATION THERAPY

Principles

• Consider unit-specific antibiograms in choosing initial appropriate therapy.

• Certain antibiotics promote resistance to other classes of antibiotics.–Choose agents that minimize resistance.–Consider the impact of outpatient antibiotic

therapy on in-patient antibiotic resistance.

• Choose combination therapy in appropriate settings, such as Third-generation cephalosporins for Enterobacter.

Antibiotic Susceptibility of Resistant Klebsiella pneumoniae

Paterson DL. IDSA 1998.

Piperacillin-sensitive and Piperacillin–resistant P. aeruginosa VAP

• Epidemiologic investigation of ICU patients who developed VAP caused by P. aeruginosa, with 34 isolates being piperacillin resistant and 101 being piperacillin sensitive.

• Independent risk factors for piperacillin resistance:– Underlying fatal medical condition– Initial disease severity– Previous fluoroquinolone use.

• “Restricted fluoroquinolone use is the sole independent risk factor for PRPA* VAP that is open to medical intervention.”

*Piperacillin-resistant P. aeruginosa

Trouillet JL et al. Clin Infect Dis 2002;34:1047-1054.

Mortality and Inadequate Therapy in Enterobacter

In a study of 129 patients with Enterobacter bacteremia:• 63% (7/11) patients who received inadequate therapy died, compared

with 17% (9/54) patients who received adequate monotherapy and 16% (10/64) patients who received adequate combination therapy.

• Administration of a third-generation cephalosporin to patients who developed Enterobacter bacteremia within the past 14 days was significantly more likely to cause emergence of a multiresistant Enterobacter spp. (p<0.001) than was administration of other classes of antibiotics.

• “When Enterobacter organisms are isolated from blood, it may be prudent to avoid third-generation cephalosporin therapy regardless of in vitro susceptibility.”

Chow JW et al. Ann Internal Med 1991;115:585-590.

Treatment Outcome for ESBL-Producers

Paterson DL. IDSA 1998.

8Imipenem

36Quinolones

44Beta-Lactams

71No active antibiotics

% Mortality% MortalityTreatmentTreatment

Initial appropriate therapy should be administered empirically if there is any suspicion that an infection is due to an ESBL-producing strain.

Using Third- and Fourth-Generation Cephalosporins Against ESBL Producers

• Cephalosporins may not be effective against K. pneumoniae bacteremia

• Many labs do not seem to be able to detect ESBL- producing Enterobacteriaceae.

• Suboptimal clinical responses have been observed when third- and fourth-generation cephalosporins are used to treat ESBL-producing organisms.

Paterson DL et al. J Clin Microbiol 2001;39:2206-2212.

• All patients were ventilated > 7 days, and had received prior antibiotic therapy.

Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539.

Combination Therapy in Critically Ill Patients with VAP

Combination Therapy in Critically Ill Patients with VAP

0 50 60 70 80

Aztreonam+ amikacin+ vancomycin

Piperacillin-tazobactam + amikacin + vancomycin

Ceftazidime + amikacin+ vancomycin

Imipenem + amikacin+ vancomycin

% susceptibility90 100

Carbapenems: A Good Choice for Initial Appropriate Therapy in

ICU Patients with Serious Infection

• Broad-spectrum activity• Proven efficacy• Low potential for resistance• Good tolerability

Principles and Specifics of De-Escalating

Stage 2

DE-ESCALATION THERAPY

Stage 1 • Administering the broadest-spectrum antibiotic

therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay)

Stage 2• Focusing on de-escalating as a means to minimize

resistance and improve cost-effectiveness

General Principles When Considering De-Escalating

• Identify the organism and know its susceptibilities; recognize any limitation in the available microbiology support system (e.g., length of time to receiving antibiogram).

• Assess and potentially modify initial selection of antibiotics based on organism susceptibility report.

• Make the decision in the context of patient improvement on the initial regimen.

• Individualize the duration of therapy based on patient factors and clinical response.

How To Optimize De-Escalating: Use of Clinical Parameters To Modify or Stop

Antibiotic TherapyUse of the Clinical Pulmonary Infection Score (CPIS) toattempt to identify patients in whom antibiotic therapycan be stopped after 3 days.• Factors in the calculation of the CPIS*:

– Temperature– Blood leukocytes– Tracheal secretions– Oxygenation– Pulmonary radiography– Progression of pulmonary infiltrate– Culture of tracheal aspirateScore 6 (pneumonia unlikely)Score 6 (treat as having pneumonia)

*The first five criteria were used to calculate initial CPIS;

all 7 were use to calculate a repeat score on day 3.

Singh N et al. Am J Respir Crit Care Med 2000;162:505-511.

How To Optimize De-Escalating: Use of Clinical Parameters To Modify or Stop Therapy

• Evolution of the CPIS correlated with mortality.• PaO2/FIO2 ratio was the best correlate of clinical response and outcome.

Luna CM et al. Crit Care Med (in press).

4

5

6

7

VAP-3 VAP VAP+3 VAP+5 VAP+7

CP

IS

Survivors (n=31)

Non-Survivors (n=32)

All (n=63)

Therapy Serial CPIS Measurements to Determine the Outcome in VAP

Days

Application of a clinical guideline for treatment of VAP shownto increase the initial administration of adequate antimicrobialtreatment and decrease the overall duration of antibiotic treatment.• Before (n=50) and after (n=52) comparison of VAP management with initiation

of protocol.

• Protocol: – Clinical diagnosis of VAP with tracheal aspirate or bronchial cultures.– Before period: therapy as per treating physician. – After period: patients with VAP received antibiotic treatment according to

treatment guidelines; empiric treatment for P. aeruginosa; MRSA with vancomycin, imipenem/ciprofloxacin (selected based on local susceptibility data).

– Modify therapy per culture after 24-48 hours depending on the clinical course of the patient.

– Try to STOP therapy after 7 days unless clinically indicated otherwise.

Ibrahim EH et al. Crit Care Med 2001; 29: 1109-1115.

How To Optimize De-Escalating:Use of Protocol Therapy in VAP (1)

Probability to have antibiotics stopped earlier was 2 fold higher in

Procalcitonin

Am J Respir Crit Care Med 2008; 117: 498-505

Significantly shorter median ICU and hospital length of stay

Kaplan-Meier plots

Am J Respir Crit Care Med 2008; 117: 498-505

How To Optimize De-Escalating: The Role of Protocol Therapy in VAP (2)

Mean APACHE II = 25.6, Mean CPIS = 6.7

***

**

*P<0.030 **P<0.001***Before period (14.8+8.1 days; After period (8.6+5.1 days)

Adapted from Ibrahim EH et al. Crit Care Med 2001; 29: 1109-1115.

%

When microbiologic data are known, narrow antibiotic coverage

Kollef M. Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH., eds. Antimicrobial Optimization: Concepts and Strategies in Clinical Practice. New York:Marcel Dekker Publishers, 2005:41-64.

Treatment Duration

Treatment Duration?Treatment Duration?

• Uncomplicated UTIs – Depends on antibiotic (Single dose: gatifloxacin; 3 days:

ciprofloxacin, TMP/SMX; 7 days: nitrofurantoin, oral cephalosporins)

• Endocarditis (4- 6 weeks) • Osteomyelitis (4-6 weeks)• Catheter-related infections? Depends on organism

– S. epidermidis and line removed: 5-7 days, line not removed, 10-14 days

– S. aureus: 14 days +/- TEE

• Pneumonia– Hospital/healthcare-associated with good clinical response: 8 days

(unless etiologic pathogen is P. aeruginosa, ~10-14 days)– Assumes active therapy administered initially

Treatment Duration

No. at risk197 187 172 158 151 148

147204 194 179 167 157 151

147

8 vs 15 Day Treatment of VAPNo difference in outcome except if P. aeruginosa

involved

Pro

bab

ilit

y o

f su

rviv

al

Days after Bronchoscopy

P=0.65

Antibiotic regimen8 days15 days

JAMA 2003 290:2588

No. at risk197 187 172 158 151 148

147204 194 179 167 157 151

147

• Guidelines– IDSA (2000)—treat Streptococcus pneumoniae until

afebrile 72 hours; gram negative bacteria, Staphylococcus aureus, “atypicals” = 2 weeks

– Canadian IDS/TS (2000) = 1–2 weeks– ATS (2001)—standard is 7–14 days, but with new agents, may shorten

duration (ie, 5–7 days for outpatients)– BTS (2001)—subject to clinical judgment (7–21 days)

• Evidence– “The precise duration of treatment … is not supported

by robust evidence”–BTS– “Not aware of controlled trials”–IDSA

Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382.Mandell LA, et al. Clin Infect Dis. 2000;31:383-421.British Thoracic Society. Thorax. 2001;56 (Suppl 4): iv1-iv64.American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-1754.

Treatment Duration of Community-Associated Treatment Duration of Community-Associated Pneumonia : No ConsensusPneumonia : No Consensus

Combination Therapy

When is Combination Therapy Considered When is Combination Therapy Considered Appropriate?Appropriate?

• Initial empirical “coverage” of multi-drug resistant pathogens until culture results are available (increases chances of initial active therapy)

• Enterococci (Endocarditis, meningitis?)• P. aeruginosa (non-urinary tract = controversial; limit amino

glycoside component of combination after 5-7 days in responding patients)

• S. aureus, S. epidermidis (Prosthetic device infections, endocarditis)-Rifampin/gentamicin+ vancomycin (if MRSA or MRSE) or antistaphylococcal penicillin

• Mycobacterial infections• HIV

Prevention is better than cure

• Hand washing and hand hygiene in general are vital and fundamental aspect of infection control,

• Blocking transmission of infection, barrier nursing, interrupting progression from colonization to infection and eliminating risk factors such as invasive devices .

Summary

Summary

Initial inadequate therapy: • Inadequate initial empiric therapy leads to increased mortality

in patients with serious infection.

Initial appropriate therapy: • Means starting with a broad-spectrum antibiotic and then focusing

based on clinical and microbiological data. Broad-spectrum antibiotics should not be held in reserve.

• Should be based on patient stratification, and local epidemiology and susceptibility patterns.

• Includes use of appropriate drug, dose, and duration.

Summary (continued)

DE-ESCALATION THERAPY occurs in two stages:• Stage 1 - administering the broadest-spectrum antibiotic

therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of stay).

• Stage 2 - focusing on de-escalating as a means to minimize resistance and improve cost-effectiveness.

An Art in Medicine

Balance

An Evidence-Based Problem:

Mortality withInadequate Therapy

A Theoretical Dilemma:

Concern of Resistance withBroad-Spectrum Therapy

Evans RS et al. N Engl J Med 1998;338:232-238.Gruson D et al. Am J Respir Crit Care Med 2000;162:837-843. Raymond DP et al. Crit Care Med 2001;29:1101-1108.

Clinical evidence showing lack of resistance with heterogeneous use of broad-spectrum therapy:

Any solution to a problem changes the problem.— R. W. Johnson

Life would otherwise be boring, no?