This document discusses the importance of initial appropriate antibiotic therapy for critically ill patients with serious infections. It emphasizes that inadequate or delayed antibiotic therapy is associated with increased mortality. The principles of selecting initial empiric therapy include considering local susceptibility patterns, prior antibiotic use, and risk factors for resistance. Broad-spectrum combination therapy may be warranted initially for certain infection types and patients, with the goal of de-escalating therapy as pathogens are identified to improve outcomes while minimizing antibiotic resistance. Timely administration of antibiotics, within 1-3 hours of suspicion of infection, is also vital.
2. The war against infectious diseases
has been won.”
– Dr. William Stuart, U.S. Surgeon General,1969
In 1969……
3. 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
6. 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.
7. 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.
1
Kollef MH et al. Chest 1999;115:462-474.
2
Ibrahim EH et al. Chest 2000;118:146-155.
Initial therapy is considered to be inadequate if:
8. 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
PercentInappropriate
9. 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
12. Tackling Infections Easily?
The Pure and Simple Truth?
• The truth is rarely pure and never simple.
• So it is with tackling infections!
13. 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.
14. Sepsis: a common disease
• Incidence in US (cases per 100,000)
– AIDS1
17
– Colon and rectal cancer2
48
– Breast cancer2
112
– Congestive heart failure3
~196
– Severe sepsis4
~300
• Number of deaths in US each year
– Acute myocardial infarction5
218,000
– Severe sepsis4
215,000
1
Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.
2
American Cancer Society. 2001. Incidence rate for 1993-1997.
4
Angus DC et al. 2001. Crit Care Med 29:1303-1310.
5
National Center for Health Statistics. 2001.
15. …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
16. The light sat the end of the tunnel?
Mortality from Sepsis
Martin NEJM 2003
17. 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”
18. Therapeutic interventions in
Severe Sepsis: Effect on Mortality
Variable Odds
Ratio
95% CI P value
Broad spectrum antibiotics
0 - 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 Sepsis
Ferrer R, Artigas A, Suarez D et al
AJRCCM 180:861-866, 2009
27. 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
33. • 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.
34. 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?
35.
36. 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.
37. Trouillet J-L. Am J Respir Crit Care Med 1998;157:531-539.
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
% susceptibility
90 100
39. 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
40. Appropriate Early Antibiotic Therapy Reduces Mortality
Rates In Patients With Suspected VAP
Iregui et al. Chest 2002;122:262–268
Mortality (%)
Hospital mortality Mortality attributed
to VAP
0
60
80
20
40
p<0.01
p<0.001
Initially delayed
antibiotic treatment
Early appropriate
antibiotic treatment
41. • 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
42. 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.
43. 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
44. Antibiotic Pharmacology and theAntibiotic Pharmacology and the
Pharmacodynamics of Bacterial KillingPharmacodynamics of Bacterial Killing
47. 2 gm IV of Cefoperazone results in
higher Cmax
Drugs 1981;22 (Suppl 1):35-45
48. 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
49. 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.
50. 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
51. 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,
52. 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
53. Which Patients Are Candidates
For
Initial Aggressive
Antibiotic Therapy?
54. 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
55. What are the Principles
in Choosing the Initial
Appropriate Empiric Therapy?
Stage 1
56. 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
57. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. • 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
0 50 60 70 80
Aztreonam+ amikacin
+ vancomycin
Piperacillin-tazobactam
+ amikacin + vancomycin
Ceftazidime + amikacin
+ vancomycin
Imipenem + amikacin
+ vancomycin
% susceptibility
90 100
64. 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
66. 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
67. 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.
68. How To Optimize De-Escalating: Use of
Clinical Parameters To Modify or Stop
Antibiotic Therapy
Use of the Clinical Pulmonary Infection Score (CPIS) to
attempt to identify patients in whom antibiotic therapy
can 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 aspirate
Score ≤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.
69. 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
CPIS
Survivors (n=31)
Non-Survivors (n=32)
All (n=63)
Therapy Serial CPIS Measurements to Determine the Outcome in VAP
Days
70. Application of a clinical guideline for treatment of VAP shown
to increase the initial administration of adequate antimicrobial
treatment 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)
71. Probability to have antibiotics
stopped earlier was 2 fold higher in
Procalcitonin
Am J Respir Crit Care Med 2008; 117: 498-505
72. Significantly shorter median ICU
and hospital length of stay
Kaplan-Meier plots
Am J Respir Crit Care Med 2008; 117: 498-505
73. 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.
%
74. 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.
76. 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
77. • 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
78. No. at risk
197 187 172 158 151 148
147
204 194 179 167 157 151
147
8 vs 15 Day Treatment of VAP
No difference in outcome except if P. aeruginosa
involved
Probabilityofsurvival
Days after Bronchoscopy
P=0.65
Antibiotic regimen
8 days
15 days
JAMA 2003 290:2588
No. at risk
197 187 172 158 151 148
147
204 194 179 167 157 151
147
79. • 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”–IDSABartlett 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-AssociatedTreatment Duration of Community-Associated
Pneumonia : No ConsensusPneumonia : No Consensus
81. When is Combination Therapy ConsideredWhen 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
82. 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 .
84. 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.
85. 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.
86. An Art in Medicine
Balance
An Evidence-Based Problem:
Mortality with
Inadequate Therapy
A Theoretical Dilemma:
Concern of Resistance with
Broad-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:
87. Any solution to a problem
changes the problem.
— R. W. Johnson
Life would otherwise be
boring, no?
Editor's Notes
Initial inadequate antimicrobial therapy usually results from a failure to suspect infections caused by antibiotic-resistant organisms.
There must be a high index of suspicion on the part of practitioners caring for critically ill patients in order to consider the diagnosis of infection in a timely manner.
In contrast to initial appropriate therapy, initial inadequate therapy can be defined as any therapeutic regimen, including lack of a regimen, that did not effectively treat an infection. The inadequacy of a therapy can only be classified with certainty at the time of microbiological documentation of the infection.
Typically, initial inadequate therapy would be prescribed because the infecting pathogen had not yet been identified, or because the susceptibility profile of the pathogen was not known.10
Unfortunately, not all patients receive appropriate antimicrobial treatment
In this prospective study of 2,000 patients admitted to an intensive care unit, 655 patients had 1 or more infections
Treatment of 17.1% of those with community-acquired infection was inappropriate; 34.3% of those with hospital-acquired infection was inappropriate; and 45.2% of those with a hospital-acquired infection complicating a community-acquired infection was inappropriate
In the early and mid-1990s, several studies were published which suggested that the appropriateness of initial antibiotic therapy was a major factor in hospital mortality rates.7-11 These studies found that patients who did not receive appropriate initial therapy had higher hospital mortality rates than those patients who received empiric therapy that provided full antimicrobial coverage.1 Moreover, once therapy was initiated, switching from inadequate to appropriate therapy did not lower mortality rates.7,9,12,13 In other words, the consequences of initial inadequate therapy were irreversible.
Later publications confirmed these findings.2,14
Initial appropriate therapy is a risk factor that can be controlled by taking appropriate action. Selection of initial therapy can thus represent an opportunity to reduce mortality. If initial antibiotic therapy is crucial to patient survival, what, then, constitutes initial appropriate therapy?
A single-center, prospective, 25-month study of 135 consecutive episodes of VAP was conducted to determine the risk factors for VAP caused by suspected drug-resistant bacteria.22 Patients were grouped according to prior duration of mechanical ventilation (MV &lt; 7 or &gt; 7 days) and prior use or lack of use (within 15 days) of antibiotics.
Patients who required MV for &gt; 7 days and had received prior antibiotic therapy had VAP that was mainly caused by multiresistant bacteria including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and methicillin-resistant Staphylococcus aureus (MRSA).
The authors concluded that two main risk factors for selecting potentially resistant bacteria responsible for VAP were the duration of MV before the onset of VAP and recent use (within 15 days) of antibiotics.22
The graph above indicates the effect of combination therapy in patients who had undergone prolonged MV (&gt; 7 days) and received recent antimicrobial treatment. The greatest percentage of pathogens was susceptible to a combination of imipenem, amikacin, and vancomycin.
It is essential to understand local susceptibility patterns in order to optimize treatment.
Objective :
To compare T&gt;MIC of meropenem when administered as 1 gm vs. 2gm by a 3 hr infusion in patients with suspected VAP caused due to pathogens with intermediate resistance to meropenem.
N= 9 patients with VAP.
Conclusion
For infections caused by pathogens with intermediate resistance, a 3 hr infusion of 2 g meropenem every 8hr can provide concnetartion in serum above the MIC of 16 mcg/mL for almost 60 % of an 8h interval.
Given the increased mortality rates associated with initial inadequate therapy, it would be useful to identify those patients with HAP or VAP for whom initial appropriate therapy is most important. The American Thoracic Society (ATS) has issued treatment guidelines, basing treatment recommendations on severity of illness and underlying risk factors.4
It is important to consider antibiotic resistance in the treatment of patients with HAP or VAP. Antibiotic resistance is an important factor in treatment failure. A treatment approach which uses appropriate initial therapy avoids the problem of administering inadequate therapy to patients who are infected with resistant pathogens or who are predisposed to resistance.13
There are also many risk factors for mortality in these patients. Some of these risk factors, such as age, do not allow for intervention. Other risk factors, such as use of inadequate initial therapy, can be ameliorated. The key is early identification of patients who require empiric therapy with a broad-spectrum antibiotic, and administration of initial appropriate therapy to these patients without delay.
Stratifying patients for treatment according to ATS guidelines, avoiding antibiotic resistance, and identifying the risk factors for mortality in patients with HAP will be discussed in the next slides in order to clarify which patients would benefit from initial aggressive, broad-spectrum, empiric therapy.
The importance of initial appropriate therapy for critically ill patients with serious infection is clear. The key is to choose the best initial empiric therapy that will cover the infecting pathogens. This means that the pathogens most likely to be responsible for HAP must be identified overall, and in each institution.
Paterson et al. created the susceptibility graph above.40 ICU isolates of Klebsiella pneumoniae typically harbor a high rate of resistance. This study found that 43% of ICU-acquired isolates were resistant. In sharp contrast to the other antibiotics tested, no resistance to imipenem was observed. This highlights the low potential for resistance to imipenem, even in resistant strains of Klebsiella. Another study also found that imipenem remained highly active against extended spectrum beta-lactamase (ESBL) – producing K. pneumoniae.41
The presence of ESBLs is a major reason that Klebsiella spp. are resistant to cephalosporin antibiotics. A prospective study of Klebsiella pneumoniae bacteremia due to ESBL-producing strains was conducted to examine outcomes in patients who had been treated with cephalosporins.42 The infecting pathogen was found to be susceptible or of intermediate susceptibility in vitro in each case. This study combined its results with previously published reports and found that 54% (15 of 28) of patients with serious infections due to “susceptible” Klebsiella strains who were treated with cephalosporins experienced treatment failure. Furthermore, of the five patients treated with cefepime, four experienced clinical failure.
The high level of piperacillin-tazobactam resistance among ESBL producers found in this study was corroborated by Babini et al. (2000), who demonstrated a 63% (69/110) resistance rate in 1997/1998.43
Similar to the situation with ESBL-producing K. pneumoniae, carbapenems remained active against ESBL-producing Escherichia coli strains in contrast to many cephalosporins in an in vitro study.23
The key is to use up-to-date local susceptibility data to determine what constitutes appropriate antibiotic therapy.35 In the absence of such data, in regions where ESBL-producing organisms are problematic, information such as that presented in this slide can form the basis of general treatment guidelines. For instance, using third-generation cephalosporins would not be recommended due to high-level resistance—NCCLS guidelines do not recommend their use against ESBL producers; in contrast, susceptibility to imipenem remains high where ESBL-producing Klebsiella is a problem.4
Paterson et al. found that the highest mortality rates occurred with antibiotics that were inactive in vitro against ESBL-producing organisms.40 High mortality rates also occurred when beta-lactam antibiotics or quinolones found to be active in vitro were used to treat patients with infections due to ESBL-producers.
In contrast, patients treated with imipenem experienced low mortality rates.
In a large survey of 369 American clinical microbiology laboratories, only one-third of laboratories actually tested for ESBL-producing Enterobacteriaceae, and many laboratories were unable or unwilling to perform the tests for ESBL-producing organisms.42 It is thus essential that initial appropriate therapy be administered empirically if there is any suspicion that an infection is due to an ESBL-producing strain.
Paterson et al. (2001) conducted a prospective study of patients with K. pneumoniae bacteremia.42 A total of 85 of 455 episodes were due to ESBL-producing K. pneumoniae; 10 of the patients were treated with cephalosporins to which the organisms is not resistant .
A clinical failure was observed in two out of three cefepime-treated patients with bacteremia due to an ESBL-producing strain of K. pneumoniae, even though the strains were susceptible in vitro.
ESBL-producing organisms with MICs in the susceptible range in vitro may not truly be susceptible in patients with serious infections. In this study, for instance, the MIC at standard inoculum levels (105 CFU/mL) was 1 g/mL for cefepime, compared with an MIC of &gt;64 g/mL at higher inoculum levels (107 CFU/mL). This has been referred to as the “inoculum effect,” where the greater the concentration of pathogen, the higher the drug MIC becomes. This may be the case with cefepime, and the reason that the majority of patients in this study failed therapy with cefepime even though the infecting pathogen appeared to be susceptible in vitro.
A single-center, prospective, 25-month study of 135 consecutive episodes of VAP was conducted to determine the risk factors for VAP caused by suspected drug-resistant bacteria.16 Patients were grouped according to prior duration of mechanical ventilation (MV &lt; 7 or &gt; 7 days) and prior use or lack of use (within 15 days) of antibiotics.
Patients who required MV for &gt; 7 days and had received prior antibiotic therapy had VAP that was mainly caused by multiresistant bacteria including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and methicillin-resistant Staphylococcus aureus (MRSA).
The authors concluded that two main risk factors for selecting potentially resistant bacteria responsible for VAP were the duration of MV before the onset of VAP and recent use (within 15 days) of antibiotics.16
The graph above indicates the effect of combination therapy in patients who had undergone prolonged MV (&gt; 7 days) and received recent antimicrobial treatment. The greatest percentage of pathogens was susceptible to a combination of imipenem, amikacin, and vancomycin.
The second stage of DE-ESCALATION THERAPY™ involves the decision to de-escalate to a narrower spectrum antibiotic in order to avoid the emergence of resistance and provide a more cost-effective treatment. The process of de-escalating will be discussed in the following slides.
Clinical Pulmonary Infection Scores (CPIS) was used in an observational cohort study of six critical care units in Buenos Aires, Argentina, to identify early in the course of VAP which patients are responding to therapy.63 This study enrolled 427 consecutive patients who were receiving mechanical ventilation &gt;72 hours. A total of 63 patients had two of three clinical criteria of VAP and positive bacteriological cultures. Patients were monitored daily, and CPIS were analyzed 3 days prior to VAP, onset of VAP, and 3, 5 and 7 days after VAP onset.
A time-dependent analysis of the CPIS was conducted for the overall population and independently for the 31 survivors and for the 32 nonsurvivors. In the overall population. CPIS score worsened significantly at the onset of VAP compared to the CPIS present 3 days before (p&lt;0.001). Comparing survivors with nonsurvivors, the CPIS score was very similar in both groups at 3 days before onset of VAP and VAP onset time points. After the VAP onset time point, the CPIS score exhibited a different behavior in survivors and nonsurvivors.
CPIS was found to correlate with mortality. The PaO2/FiO2 ratio was the best correlate of clinical response and outcome.
Probability to have antibiotics stopped earlier was 2 fold higher in PCT
A measure of how often a particular event happens in one group compared to how often it happens in another group, over time. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups.
However patients who were randomized to the PCT group had a significantly shorter median ICU and hospital length of stay
This study showed that when a clinical guideline for the treatment of VAP was used, adequate initial antimicrobial treatment was statistically more likely to occur, the overall duration of antimicrobial treatment for patients with suspected VAP was significantly reduced, and a second episode of VAP was found to occur less often.19
It should be recognized that protocol-driven therapy has limitations; specifically, it may lead to homogeneity of antibiotic use.
The second stage of DE-ESCALATION THERAPY™ involves the decision to de-escalate to a narrower spectrum antibiotic in order to avoid the emergence of resistance and provide a more cost-effective treatment. The process of de-escalating will be discussed in the following slides.
The preceding slides have illustrated that the weight of evidence shows that inappropriate antibiotic therapy is associated with higher mortality rates.
Evans et al. suggested that a consensus exists that excessive antibiotic use can lead to resistance problems.16 Simply using broad-spectrum antibiotics appropriately does not lead to resistance, however.
Based on a questionnaire administered to 100 intensivists, Rello et al. found a high degree of non-adherence to pharmacologic guidelines among 110 opinion leaders from 22 countries, regardless of the strength of evidence to support the guidelines.70
This slide shows the important interaction between clinical trial evidence and physician experience in treating patients. It does not make sense to take a theoretical approach based on anecdotal beliefs when there is evidence to support a rational approach.
