Download Insert Slide Title Here - Academy for Infection Management

Educational slide resource kit
Supported by an educational grant from AstraZeneca
February 2004
© Academy for Infection Management 2004 (All Rights Reserved)
Contents
• Academy for Infection Management (AIM)
concept, objectives and core principles
• Use of appropriate antibiotics early in nosocomial
infections: reviewing the evidence
• Pharmacokinetic/pharmacodynamic considerations for
antibiotic therapy and clinical implications
• Importance and mechanisms of antibiotic resistance
• Impact of inappropriate antibiotic treatment on health
economic outcomes
Educational slide resource kit
AIM concept, objectives and
core principles
AIM concept and objectives
Concept
• Use of appropriate antibiotics early in nosocomial infections
to improve outcomes (mortality, morbidity and length of stay in
hospital)
Objectives
• Provide a global educational resource for physicians
(infectious disease specialists, surgeons, chest
physicians, microbiologists) involved in the treatment of
nosocomial infections
• Share best clinical practice
• Share the latest clinical and scientific data on
nosocomial infection management with regard to
improving patient outcomes
AIM core faculty
• Marin H Kollef (Chairperson)
• Gilbert R Park
• Philip S Barie
• David Paterson
• John Bradley
• Giovanni Di Perri
• Mark A Malangoni
• Jordi Rello
• Robert G Masterton
• Andrew Shorr
• John E McGowan Jr
• Norbert Suttorp
• Peggy S McKinnon
• Jose M Tellado
• David P Nicolau
• Tobias Welte
• Michael S Niederman
• Martin J Wood
AIM educational programme:
core principles
• Multidisciplinary faculty have developed the
core principles of the Academy, which concern
the following topics:
– patient outcomes
– antibiotic choice
– resistance
– infection control
AIM core principles
Patient outcomes
• Select the most appropriate antibiotic depending
on the patient, risk factors, suspected infection
and resistance
Antibiotic choice
• It is important to start with the appropriate empiric
antibiotic first in nosocomial infections
• Administer antibiotics at the right dose for the
appropriate duration
• If appropriate, change antibiotic dosage or therapy
based on resistance and pathogen information
AIM core principles
Resistance
• Recognise that prior antimicrobial administration is a
risk factor for the presence of resistant pathogens
• Know the unit’s resistance profile and choose
antibiotics accordingly
Infection control
• Wash hands adequately and wear gloves appropriately
• Remove indwelling devices as soon as they are no
longer indicated
AIM educational programme:
delivery vehicles
• Global educational summit meetings
• Regional, national and local meetings
• Core principles and supporting evidence
• Case studies (slides and key question workmats)
– intensive care, hospital-acquired pneumonia, serious surgical infections
• Educational slide resource kit and paper summaries
• Antibiotic policy workshop
– exercise to examine the external constraints that influence hospital
antibiotic guidelines policy
• Website (www.infectionacademy.org)
– provides access to all educational materials
Educational slide resource kit
Use of appropriate antibiotics early in
nosocomial infections: reviewing the evidence
Potential consequences of inappropriate
antibiotic therapy
• Inappropriate empiric antibiotic therapy can
lead to increases in:
– mortality
– morbidity
– length of hospital stay
– cost burden
– resistance selection
Inappropriate antibiotic therapy
• Inappropriate antibiotic therapy can be defined
as one or more of the following:
– ineffective empiric treatment of bacterial infection
at the time of its identification
– the wrong choice, dose or duration of therapy
– use of an antibiotic to which the pathogen
is resistant
Evidence of improved clinical outcomes with
appropriate empiric antibiotic therapy
• A number of studies have demonstrated
the benefits of early use of appropriate
empiric antibiotic therapy for patients with
nosocomial infections
• Several key clinical studies are reviewed in the
following slides
Inappropriate antibiotic therapy is a risk factor
for mortality among patients in the intensive
care unit (ICU)
• Infection-related mortality rates were assessed in a
prospective cohort, single-centre study of 2000
patients admitted to medical/surgical ICUs
• 655 patients had a clinically recognised infection:
– 442 (67.5%) had a community-acquired infection
– 286 (43.7%) developed a nosocomial infection
– 73 (11.1%) had both community-acquired and nosocomial
infections
• 169 (25.8%) patients received inappropriate initial
antimicrobial treatment
Kollef et al. Chest 1999;115:462–474
Inappropriate antibiotic therapy is a risk factor
for mortality among patients in the ICU
Hospital mortality (%)
60
p<0.001
Inappropriate therapy
Appropriate therapy
p<0.001
50
40
30
20
10
0
All causes
Infectious disease-related
Mortality type
Kollef et al. Chest 1999;115:462–474
Appropriate antibiotic therapy reduces
mortality and complications in patients with
nosocomial pneumonia
• The frequency of and reasons for changing empiric antibiotics
during the treatment of hospital-acquired pneumonia were
assessed in a prospective multicentre study across
30 Spanish hospitals
• Of the 16 872 patients initially enrolled, 530 developed
565 episodes of pneumonia after ICU admission
• Empiric antibiotics (administered in 490 [86.7%] of episodes)
were modified in 214 (43.7%) cases because of:
– isolation of micro-organism not covered by treatment (62.1%)
– lack of clinical response (36.0%)
– development of resistance (6.6%)
Alvarez-Lerma et al. Intensive Care Med 1996;22:387–394
Appropriate antibiotic therapy reduces
mortality and complications in patients with
nosocomial pneumonia
Attributable mortality
Appropriate
therapy
(n=284)
Inappropriate
therapy
(n=146)
p-value
16.2%
24.7%
0.04
2.25 ± 1.98
<0.001
No. complications/patient 1.73 ± 1.82
Shock
17.1%
28.8%
<0.005
Gastrointestinal bleeding
10.7%
21.2%
0.003
Respiratory failure
24.9%
32.2%
NS
Multiple organ failure
12.5%
21.2%
NS
Extrapulmonary infection
13.2%
17.1%
NS
Alvarez-Lerma et al. Intensive Care Med 1996;22:387–394
Appropriate early antibiotic therapy reduces mortality
rates in patients with suspected ventilator-associated
pneumonia (VAP) (Study 1)
• A prospective observation and bronchoscopy study
of
patients with VAP assessed the impact of
bronchoalveolar lavage (BAL) data on the selection of
antibiotics and clinical outcomes in a medical/surgical ICU
• 132 mechanically ventilated patients (hospitalised
>72 hours) with clinically confirmed VAP underwent
BAL within 24 hours of diagnosis
– 107 patients received antibiotics prior to bronchoscopy
– 25 patients received antibiotics immediately after
bronchoscopy
• Mortality rates were assessed in relation to the adequacy
and time of initiation of antibiotic therapy
Luna et al. Chest 1997;111:676–685
Appropriate early antibiotic therapy reduces
mortality rates in patients with suspected VAP
(Study 1)
Mortality (%)
100
p<0.001
80
No antibiotic
Appropriate antibiotic
Inappropriate antibiotic
60
40
20
0
Pre-BAL
Post-BAL
Post-culture
result
Luna et al. Chest 1997;111:676–685
Appropriate early antibiotic therapy reduces
mortality rates in patients with suspected VAP
(Study 2)
• A prospective study of 113 patients with VAP assessed the
utility of microbiological investigations in guiding/modifying
antibiotic prescription and their influence on clinical outcome
• Microbial investigations included:
– blood culture (78.7% of cases)
– culture of protected brush specimens (95.5% of cases)
– BAL culture (45.5% of cases)
• Immediately after diagnosis, empiric antibiotic therapy was
either initiated or modified
• Antibiotic therapy could subsequently be changed based
on culture and susceptibility studies
Rello et al. Am J Respir Crit Care Med 1997;156:196–200
Appropriate early antibiotic therapy reduces
mortality rates in patients with suspected VAP
(Study 2)
Mortality (%)
40
p<0.05
30
• Excess mortality caused
by inappropriate initial
therapy was estimated
to be 21.4%
(95% CI, 43.2 to -0.03)
20
10
0
Appropriate initial
antibiotic
Inappropriate initial
antibiotic
Rello et al. Am J Respir Crit Care Med 1997;156:196–200
Appropriate early antibiotic therapy reduces
mortality rates in patients with suspected VAP
(Study 3)
• The influence of initially delayed appropriate antibiotic
therapy (IDAAT) was assessed in a study of 107 patients
with VAP in a medical ICU
• All 107 patients received an antibiotic shown to be active
in vitro against the bacterial pathogens isolated from
respiratory secretions:
– 33 patients received treatment that was delayed for 24 hours
(mean  SD; 28.6  5.8 hours) after meeting diagnostic criteria for
VAP (classified as receiving IDAAT)
– 74 patients received treatment within 24 hours
(mean  SD; 12.5  4.2 hours) of meeting diagnostic criteria for
VAP
• Independent risk factors for hospital mortality were assessed
Iregui et al. Chest 2002;122:262–268
Appropriate early antibiotic therapy reduces
mortality rates in patients with suspected VAP
(Study 3)
Mortality (%)
80
p<0.01
60
Early appropriate
antibiotic treatment
Initially delayed
antibiotic treatment
p<0.001
40
20
0
Hospital mortality
Mortality attributed
to VAP
Iregui et al. Chest 2002;122:262–268
Appropriate early antibiotic therapy reduces
mortality rates and length of hospital stay in
patients with bloodstream infection (Study 1)
• An observational prospective cohort study of patients
with bloodstream infection examined whether
appropriate antibiotic therapy improved survival rate
• Of the 3413 evaluable patients, 2158 (63%) received
early appropriate antibiotics
– defined as starting within 2 days of the first positive blood
culture, and if the causative pathogen was susceptible
in vitro to the administered drug
• Mortality rates and median duration of hospital stay for
surviving patients were determined
Leibovici et al. J Intern Med 1998;244:379–386
Appropriate early antibiotic therapy reduces
mortality rates and length of hospital stay in
patients with bloodstream infection (Study 1)
Mortality rate
Median duration of
hospital stay
Appropriate
therapy
(n=2158)
Inappropriate
therapy
(n=1255)
p-value
20.2%
34.4%
0.0001
9 days
(range 0–117)
11 days
(range 0–209)
0.0001
Leibovici et al. J Intern Med 1998;244:379–386
Appropriate early antibiotic therapy reduces
mortality rates in patients with bloodstream
infection (Study 2)
• A prospective cohort study evaluated the relationship
between adequacy of antibiotic treatment for
bloodstream infections and clinical outcomes among
patients admitted to a medical/surgical ICU
• 492 patients identified as having a bloodstream
infection were included in the analysis:
– 193 (39.2%) had a community-acquired infection
– 291 (59.1%) developed a nosocomial infection
– 8 (1.6%) had a community-acquired infection followed by
nosocomial infection
• Hospital mortality rates were determined
Ibrahim et al. Chest 2000;118:146–155
Appropriate early antibiotic therapy reduces
mortality rates in patients with bloodstream
infection (Study 2)
Mortality (%)
70
p<0.001
60
50
40
30
20
10
0
Appropriate initial
antibiotic
Inappropriate initial
antibiotic
Ibrahim et al. Chest 2000;118:146–155
Appropriate early antibiotic therapy reduces
mortality rates in patients with bloodstream
infection (Study 3)
• 843 episodes of positive blood cultures from
707 patients with septicaemia were reviewed in
a retrospective analysis
• Appropriate antibiotic therapy and septicaemiaassociated mortality rates were assessed at
three timepoints:
– on initiation of empiric therapy
– after a positive culture was reported
– after pathogen susceptibility results were available
• 78% of patients received appropriate antibiotic therapy
at all timepoints
Weinstein et al. Clin Infect Dis 1997;24:584–602
Appropriate early antibiotic therapy reduces
mortality rates in patients with bloodstream
infection (Study 3)
Mortality (%)
35
30
RR = 3.18
RR = 2.46
25
20
15
10
RR = 1.0
5
65/620
0
Appropriate therapy
at all timepoints
RR = relative risk of death
8/31
3/9
Appropriate therapy
only after susceptibility
determined
Inappropriate therapy
at all timepoints
Weinstein et al. Clin Infect Dis 1997;24:584–602
Summary
• Clinical evidence suggests that early use of
appropriate empiric antibiotic therapy improves
patient outcomes in terms of:
– reduced mortality
– reduced morbidity
– reduced duration of hospital stay
Educational slide resource kit
Pharmacokinetic/pharmacodynamic
considerations for antibiotic therapy
and clinical implications
Pharmacokinetic/pharmacodynamic
considerations
• The goal of antibiotic therapy is to achieve complete
bacterial eradication and to minimise the risk of
resistance selection
• The dosing regimen for a particular antibiotic is
influenced by its pharmacokinetic (PK) profile and
the susceptibility of the target pathogen
• PK/pharmacodynamic (PD) models can be used to
predict bacteriological and clinical efficacy and help
to identify the correct dose and dosing interval
PK/PD considerations
• The bactericidal activity of an antibiotic can be time
or concentration dependent
• Bacteriological efficacy also depends on the
persistence of the drug effect after serum levels have
fallen below the minimum inhibitory concentration
(MIC) for the target pathogen (post-antibiotic
effect [PAE])
• Prolonged exposure to suboptimal concentrations of
antibiotics can lead to incomplete bacterial eradication
and selection of resistance
• Penetration into target tissues is very important
PD profiling of antibiotics
• Time-dependent killing
– time above MIC (T>MIC)
• Concentration-dependent killing
– area under the concentration–time curve
(AUC):MIC ratio
– peak serum concentration (Cmax):MIC ratio
• PAE
PK/PD parameters affecting antibiotic
efficacy in vivo
Concentration
Cmax:MIC
AUC:MIC
MIC
T>MIC
0
PAE
Time (hours)
PD parameters predictive of outcome
Parameter
correlating
with efficacy
T>MIC
AUC:MIC
Cmax:MIC
Penicillins
Cephalosporins
Carbapenems
Macrolides
Azithromycin
Fluoroquinolones
Ketolides
Fluoroquinolones
Aminoglycosides
Organism kill Time-dependent
Concentrationdependent
Concentrationdependent
Therapeutic
goal
Maximise
exposure
Maximise
exposure
Examples
Optimise duration
of exposure
Drusano & Craig. J Chemother 1997;9:38–44
Drusano et al. Clin Microbiol Infect 1998;4 (Suppl. 2):S27–41
Vesga et al. 37th ICAAC 1997
Aminoglycosides
• Cmax:MIC 10 translates into improvements in
the rate and extent of clinical response
• Once-daily administration is advocated to
maximise efficacy and minimise potential drug
accumulation and toxicity
Moore et al. J Infect Dis 1987;155:93–99
Kashuba et al. Antimicrob Agents Chemother 1999;43:623–629
Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655
Fluoroquinolones
• For nosocomial pneumonia treated with ciprofloxacin,
AUC:MIC >125 results in clinical cure and
bacteriological eradication rates >80%
• For community-acquired pneumonia treated with
levofloxacin or gatifloxacin, AUC:MIC >34 improves
probability of pneumococcal bacteriological eradication
Forrest et al. Antimicrob Agents Chemother 1993;37:1073–1081
Ambrose et al. Antimicrob Agents Chemother 2001;45:2793–2797
-Lactams
• High or frequent dosing is used to optimise
T>MIC and improve clinical response and
bacteriological eradication
– may incur increased labour and drug costs
• Based on PD profiling, the antibiotic with the best
in vivo potency can be selected by integrating
available microbiological potency data and the
PK profile of the agent(s) concerned
• Prolongation of administration can enhance the
PD profile of these agents
Nicolau et al. Antimicrob Agents Chemother 2000;44:1291–1295
Craig & Andes. Pediatr Infect Dis J 1996;15:255–259
Schentag et al. Am J Med 1984;77:43–50; Grant et al. Pharmacotherapy 2002;22:471–483
-Lactams: optimising exposure
• The optimum level of exposure varies for
different agents within the -lactam class:
approximately T>MIC of:
~ 60–70% for cephalosporins
~ 50% for penicillins
~ 40% for carbapenems
Drusano. Clin Infect Dis 2003;36(Suppl. 1):S42–S50
Resistance prevention
• Use PK/PD considerations to optimise the
bacterial killing potential of antibiotic therapy
• Dead bugs don’t mutate!
Probability of developing resistance
Probability of remaining
susceptible (%)
100
AUC0–24h:MIC 100
80
60
40
Data from 107 acutely ill patients with
nosocomial RTIs treated with 5 different
antibiotic regimens (ciprofloxacin,
cefmenoxime, ceftazidime, ciprofloxacin plus
piperacillin, ceftazidime plus tobramycin)
20
0
0
5
10
15
Days from initiation of therapy
AUC0–24h:MIC <100
20
Thomas et al. Antimicrob Agents Chemother 1998;42:521–527
Summary
• PK/PD considerations provide the opportunity for
clinicians to prescribe currently available antibiotics
according to regimens that maximise bacteriological
eradication and clinical outcomes and minimise
resistance selection, ie administration of appropriate
antibiotics at the right dose for the appropriate duration
Educational slide resource kit
Importance and mechanisms of antibiotic resistance
Antibiotic resistance considerations
• Antibiotic resistance is an increasingly important
problem to consider when managing nosocomial
infections
• This section of the slide kit is intended to provide
a background to:
– epidemiology of antibiotic resistance
– antibiotic mode of action
– mechanisms of antibiotic resistance, with a focus on
-lactam resistance
– clinical impact of resistance
Epidemiology of antibiotic resistance
• The frequency of detection of antibiotic-resistant
pathogens in nosocomial infections has increased at
an alarming rate over the past few years
• 50–60% of the >2 million nosocomial infections
occurring in the USA each year are caused by
antibiotic-resistant bacteria
• The high rate of antibiotic resistance increases
morbidity, mortality and costs associated with
nosocomial infections
Jones. Chest 2001;119:397S–404S
Weinstein. Emerg Infect Dis 1998;4:416–420
Antibiotic mechanisms of action
• Antibiotic mode of action falls into the following
categories:
– cell wall synthesis inhibitors
– protein synthesis inhibitors
– nucleic acid synthesis inhibitors
– cytoplasmic membrane function inhibitors
– other agents that affect DNA
Cell wall synthesis inhibitors
• Antibiotics that inhibit bacterial cell wall
synthesis include:
– -lactams: penicillins, cephalosporins,
carbapenems, monobactams
– glycopeptides: vancomycin, teicoplanin
– cycloserine
– bacitracin
Protein synthesis inhibitors
• Antibiotics that inhibit bacterial protein
synthesis include:
– aminoglycosides: gentamicin, tobramycin, amikacin,
netilmicin, streptomycin
– tetracyclines
– MLS group: macrolides (eg erythromycin),
lincosamides, streptogramins
(eg quinupristin–dalfopristin)
– chloramphenicol
– fusidic acid
– oxazolidinones
Nucleic acid synthesis inhibitors
• Antibiotics that inhibit bacterial nucleic acid
synthesis include:
– precursor synthesis inhibitors: sulphonamides,
trimethoprim
– DNA replication inhibitors: quinolones
– RNA polymerase inhibitors: rifampicin
Other antibacterial agents
• Antibiotics with a mode of action that does not
fit into any of the previous categories include:
– cytoplasmic membrane function inhibitors:
polymixins
– other agents that affect DNA: nitroimidazoles
Resistance to antibacterial agents
• Antibiotic resistance either arises as a result of
innate consequences or is acquired from other
sources
• Bacteria acquire resistance by:
– mutation: spontaneous single or multiple changes
in bacterial DNA
– addition of new DNA: usually via plasmids, which
can transfer genes from one bacterium to another
– transposons: short, specialised sequences of DNA
that can insert into plasmids or bacterial
chromosomes
Mechanisms of antibacterial resistance (1)
• Structurally modified antibiotic target site,
resulting in:
– reduced antibiotic binding
– formation of a new metabolic pathway preventing
metabolism of the antibiotic
Structurally modified antibiotic target site
Antibiotics normally bind to specific binding
proteins on the bacterial cell surface
Antibiotic
Binding
Target site
Cell wall
Interior of organism
Structurally modified antibiotic target site
Antibiotics are no longer able to bind to modified
binding proteins on the bacterial cell surface
Antibiotic
Modified target site
Cell wall
Changed site: blocked binding
Interior of organism
Mechanisms of antibacterial resistance (2)
• Altered uptake of antibiotics, resulting in:
– decreased permeability
– increased efflux
Altered uptake of antibiotics: decreased permeability
Antibiotics normally enter bacterial cells via
porin channels in the cell wall
Antibiotic
Porin channel
into organism
Cell wall
Interior of organism
Altered uptake of antibiotics: decreased permeability
New porin channels in the bacterial cell wall do
not allow antibiotics to enter the cells
Antibiotic
New porin channel
into organism
Cell wall
Interior of organism
Altered uptake of antibiotics: increased efflux
Antibiotics enter bacterial cells via porin
channels in the cell wall
Antibiotic
Porin channel
through cell wall
Entering
Entering
Cell wall
Interior of organism
Altered uptake of antibiotics: increased efflux
Once antibiotics enter bacterial cells, they are
immediately excluded from the cells
via active pumps
Antibiotic
Porin channel
through cell wall
Entering
Exiting
Cell wall
Interior of organism
Active pump
Mechanisms of antibacterial resistance (3)
• Antibiotic inactivation
– bacteria acquire genes encoding enzymes that
inactivate antibiotics
• Examples include:
– -lactamases
– aminoglycoside-modifying enzymes
– chloramphenicol acetyl transferase
Antibiotic inactivation
Inactivating enzymes target antibiotics
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Antibiotic inactivation
Enzymes bind to antibiotic molecules
Enzyme
binding
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Antibiotic inactivation
Enzymes destroy antibiotics or prevent binding to target sites
Antibiotic
destroyed
Antibiotic altered,
binding prevented
Antibiotic
Enzyme
Target site
Cell wall
Interior of organism
Many pathogens possess multiple
mechanisms of antibacterial resistance
Modified target
Altered uptake
Drug inactivation
-lactam
+
+
++
Glycopeptide
+
Aminoglycoside
–
+
++
Tetracycline
–
+
Chloramphenicol
–
Macrolide
++
Sulphonamide
++
–
Trimethoprim
++
–
Quinolones
–
+
+
Focus on -lactam antibiotic resistance
mechanisms
• Three mechanisms of -lactam antibiotic
resistance are recognised:
– reduced permeability
– inactivation with -lactamase enzymes
– altered penicillin-binding proteins (PBPs)
Multiple antibiotic resistance
mechanisms: the -lactams
-lactam antibiotic resistance
• AmpC and extended-spectrum -lactamase
(ESBL) production are the most important
mechanisms of -lactam resistance in
nosocomial infections
• The antimicrobial and clinical features of these
resistance mechanisms are highlighted in the
following slides
-lactam resistance:
AmpC -lactamase production
• Worldwide problem:
– incidence increased from 17−23% between 1991 and 2001
in UK
• Very common in Gram-negative bacilli
• AmpC gene is usually sited on chromosomes, but can
be present on plasmids
• Enzyme production is either constitutive (occurring all
the time) or inducible (only occurring in the presence
of the antibiotic)
Pfaller et al. Int J Antimicrob Agents 2002;19:383–388
Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27
Antimicrobial features of
AmpC -lactamase
• Not inhibited by -lactamase inhibitors
• Usually confers resistance to:
– first-, second- and third-generation cephalosporins
(eg ceftazidime)
– monobactams (eg aztreonam)
– some penicillins (eg carbenicillin), less commonly
to penicillin–-lactamase inhibitor combinations
• Bacteria generally susceptible to carbapenems
and fourth-generation cephalosporins
Clinical features of AmpC -lactamase
• Constitutive mutants can be selected
during treatment
• Constitutive and induced enzyme production
can cause treatment failures
• Often creates clinical difficulties due to crossresistance with other antibiotic classes
• Can become prevalent in hospital organism
flora, causing infection control problems
AmpC production by a constitutive derepressed
mutant: resistance during therapy
Enzyme concentration
Start of antibiotic exposure
End of antibiotic exposure
Antibiotic concentration/duration of exposure
AmpC production by an induced wild-type
pathogen: natural resistance
Enzyme concentration
Start of antibiotic exposure
End of antibiotic exposure
Basal level production
Antibiotic concentration/duration of exposure
Comparison of AmpC enzyme production
Enzyme concentration
Start of antibiotic exposure
Constitutive
End of antibiotic exposure
Inducible
Basal level production
Antibiotic concentration/duration of exposure
-lactam resistance: ESBL production
• An increasing global problem
• Found in a small, expanding group of
Gram-negative bacilli, most commonly
the Enterobacteriaceae spp.
• Usually associated with large plasmids
• Enzymes are commonly mutants of TEM- and
SHV-type -lactamases
Jones et al. Int J Antimicrob Agents 2002;20:426–431
Sader et al. Diagn Microbiol Infect Dis 2002;44:273–280
Antimicrobial features of ESBLs
• Inhibited by -lactamase inhibitors
• Usually confer resistance to:
– first-, second- and third-generation cephalosporins
(eg ceftazidime)
– monobactams (eg aztreonam)
– carboxypenicillins (eg carbenicillin)
• Varied susceptibility to piperacillin/tazobactam
• Typically susceptible to carbapenems and
cephamycins
• Often clinically and/or microbiologically
non-susceptible to fourth-generation cephalosporins
Mechanism of ESBL activity
Parent -lactamase
Third-generation
cephalosporin
No fit; therefore, no enzymatic destruction of antibiotic
Mechanism of ESBL activity
ESBL
Third-generation
cephalosporin
Enzyme fit leads to destruction of antibiotic
Clinical features of ESBLs
• Even if sensitive to fourth-generation cephalosporins
in vitro, treatment failures occur in clinical practice
• Create clinical difficulties due to cross-resistance with
other antibiotic classes (eg aminoglycosides)
• Associated with nosocomial outbreaks of high
morbidity and mortality
• Result in overuse of other broad-spectrum agents
Clinical failure in the presence of ESBLs
• Recent data show high clinical failure rates among
patients treated with cephalosporins for serious
infections caused by ESBL-producing pathogens
– susceptible to cephalosporins in vitro
– 4/32 patients received cephalosporins to which pathogens
showed intermediate susceptibility and all failed treatment
– 15/28 remaining patients with cephalosporin-susceptible
pathogens failed treatment and 4 died
– 11 patients required a change in antibiotic therapy
Paterson et al. J Clin Microbiol 2001;39:2206–2212
Patients who failed cephalosporin
therapy for serious infections due to
ESBL-producing organisms
Clinical failure rate (%)
100
80
60
40
20
0
1
2
4
Cephalosporin MIC (µg/mL)
8
Paterson et al. J Clin Microbiol 2001;39:2206–2212
Features of methicillin-resistant
Staphylococcus aureus (MRSA)
• Introduction of methicillin in 1959 was followed rapidly
by reports of MRSA isolates
• Recognised hospital pathogen since the 1960s
• Major cause of nosocomial infections worldwide
– contributes to 50% of infectious morbidity in ICUs in Europe
– surveillance studies suggest prevalence has increased
worldwide, reaching 25–50% in 1997
Jones. Chest 2001;119:397S–404S
Serious infections testing positive for MRSA
isolates among hospitalised patients
(1997 SENTRY data)
Patients (%)
50
40
30
20
10
0
Pneumonia
UTI = urinary tract infection
UTI
Wound
Infection type
Bloodstream
Jones. Chest 2001;119:397S–404S
Features of MRSA: epidemic strains
• Problem escalated in the early 1980s with
emergence of epidemic strains (EMRSA)
– first recognised in the UK
– 17 EMRSAs identified to date
• Impact on hospitals is variable
– presence of EMRSA can account for >50%
of S. aureus isolates
Aucken et al. J Antimicrob Chemother 2002;50:171–175
Risk factors for colonisation or infection
with MRSA in hospitals
Prior antibiotic exposure
Admission to an ICU
Surgery
Exposure to an MRSA-colonised patient
Chambers. Emerg Infect Dis 2001;7:178–182
Emergence of MRSA in the community
• MRSA in hospitals leads to an associated rise in incidence in
the community
• Community-acquired MRSA strains may be distinct from those
in hospitals
• In a hospital-based study, >40% of MRSA infections were
acquired prior to admission
• Risk factors for community acquisition included:
–
–
–
–
recent hospitalisation
previous antibiotic therapy
residence in a long-term care facility
intravenous drug use
• Colonisation and transmission are also seen in individuals
(including children) lacking these risk factors
Hiramatsu et al. Curr Opin Infect Dis 2002;15:407–413
Layton et al. Infect Control Hosp Epidemiol 1995;16:12–17; Naimi et al. 2003;290:2976−2984
Antimicrobial features of MRSA (1)
• Mechanism involves altered target site
– new penicillin-binding protein — PBP 2' (PBP 2a)
– encoded by chromosomally located mecA gene
• Confers resistance to all -lactams
• Gene carried on a mobile genetic element —
staphylococcal cassette chromosome mec (SCCmec)
• Laboratory detection requires care
• Not all mecA-positive clones are resistant to methicillin
Hiramatsu et al. Trends Microbiol 2001;9:486–493
Berger-Bachi & Rohrer. Arch Microbiol 2002;178:165–171
Antimicrobial features of MRSA (2)
• Cross-resistance common with many other antibiotics
• Ciprofloxacin resistance is a worldwide problem
in MRSA:
– involves ≥2 resistance mutations
– usually involves parC and gyrA genes
– renders organism highly resistant to ciprofloxacin, with
cross-resistance to other quinolones
• Intermediate resistance to glycopeptides
first reported in 1997
Hiramatsu et al. J Antimicrob Chemother 1997;40:135–136
Hooper. Lancet Infect Dis 2002;2:530–538
Clinical features of MRSA
• Common associations include:
– underlying chronic disease, especially repeated
hospital stays
– prolonged/repeated antibiotics, especially the -lactams
• Usually susceptible to at least one other antibiotic
• Not all MRSAs behave as EMRSAs
• Methicillin resistance is not a marker of virulence
Clinical features of MRSA: transmission
• Occurs primarily from colonised or infected patients
via the hands of healthcare workers
– contact transmission to other patients or staff very common
• Airborne transmission important in the acquisition of
nasal carriage
• Infection control measures include:
– screening and isolation of new patients suspected of
carrying MRSA or S. aureus with vancomycin resistance
– implementing infection control programmes
– establishing adequate antibiotic policy to minimise
development of resistance
Clinical features of MRSA: outcome
• Mortality rate is higher with MRSA bacteraemia vs
methicillin-susceptible S. aureus bacteraemia
– odds ratio 1.93 (95% CI: 1.54–2.42; p<0.001)
• Potential reasons for worse outcome:
– possible enhanced virulence of the antibiotic-resistant
pathogen
– delay in appropriate antibiotic selection
– decreased effectiveness of vancomycin
• Risk of inappropriate therapy is closely associated with
poor outcome
Cosgrove et al. Clin Infect Dis 2003;36:53–59
Melzer et al. Clin Infect Dis 2003;37:1453−1460
Glycopeptide resistance in S. aureus
• MRSA infection is invariably treated with glycopeptides
– vancomycin
– teicoplanin
• However, glycopeptide resistance has recently
emerged in S. aureus
• Potential for more multi-resistant strains that will make
treatment much more difficult in the future
Management of MRSA
Treat patient with appropriate empiric
and targeted therapy
Educate on risks and control measures
Adhere to strict control measures to prevent
transmission, especially through contact
Consider clearing patient of MRSA carriage
Glycopeptide resistance: focus on
vancomycin resistance
• Vancomycin-resistant enterococci (VRE)
• Vancomycin-resistant S. aureus (VRSA)
Features of VRE
• An increasing worldwide problem:
– fourth most common cause of nosocomial infections in
the USA
• Four genotypes have been recognised — one
occurs naturally
• Acquired resistance involves multiple genes and
therefore does not arise readily
• Resistance arises through modification of the target
cell wall protein
Phenotypes of VRE
• VanA:
– most common type of VRE
– highly resistant to vancomycin and moderately resistant
to teicoplanin
– resistance is inducible
– mediated by plasmids/transposons
Phenotypes of VRE (cont’d)
• VanB:
– second most common type of VRE
– Initially, moderately to highly resistant against vancomycin
and susceptible to teicoplanin
– teicoplanin mutants readily selectable
– resistance is inducible
– gene originally present on chromosome but now
plasmid/transposon mediated
Phenotypes of VRE (cont’d)
• VanC
– resistance occurs naturally in Enterococcus gallinarum
and Enterococcus casseliflavus
– confers low level of resistance to vancomycin but
susceptibility to teicoplanin
– resistance is chromosomal
– not transferable
Phenotypes of VRE (cont’d)
• VanD
– rare cause of vancomycin resistance in
Enterococcus faecium
– highly resistant to vancomycin and low resistance
to teicoplanin
– structurally related to VanA and VanB
– resistance is inducible
– transferable
Molecular features of
vancomycin resistance
• Seven-step gene co-operation
• Involves activity of resolvase, transposase and ligase enzymes
• Alters pentapeptide precursor end sequence from
D-alanyl-D-alanine to D-alanyl-D-x, where x is lactate, serine or
other amino acid
• Or produces (vanY) tetrapeptide* that cannot bind vancomycin
Vancomycin resistance gene sequence
vanR
vanS
vanH
Detects
Produces D-Lac
glycopeptide;
switches on other genes
vanA
Produces
D-Ala-D-Lac
vanX
Cleaves
D-Ala-D-Ala
vanY
vanZ
*Cleaves
D-Ala and
D-Lac from
end chain
Exact role?
Teicoplanin
resistance?
Antimicrobial features of
resistance in VRE
• Development is slow due to very complex
gene mechanisms
• Cross-resistance between vancomycin and teicoplanin
is not absolute
• Associated with veterinary and animal husbandry use
of glycopeptides
• Resistance is transferable, largely through
bacterial conjugation
Clinical risk features for VRE infection
• Severe underlying disease
• Prolonged hospitalisation, especially in ICUs
• Previous exposure to antibiotics, especially
glycopeptides or cephalosporins
• Exposure to environment with a high prevalence
of VRE
It is important to differentiate between
COLONISATION (no clinical symptoms)
and INFECTION
Clinical features of VRE
• Organisms with reduced susceptibility to vancomycin are
associated with treatment failures
• Multiple drug resistance often associated with VRE
(eg -lactam resistance and high-level aminoglycoside
resistance)
• Teicoplanin resistance may develop in teicoplanin-susceptible,
vancomycin-resistant strains
• A rapid rise in resistance prevalence may occur,
especially in hospitals
• A strong association exists between increased vancomycin use
and increased resistance
Vancomycin resistance in S. aureus
MIC values
Acronym
NCCLS breakpoints
(mg/L)
Vancomycin-sensitive S. aureus
VSSA
4
Vancomycin-intermediate S. aureus
VISA
8–16
Vancomycin-resistant S. aureus
VRSA
32
Resistance status
NCCLS = National Committee for Clinical Laboratory Standards
Features of vancomycin resistance
in S. aureus
• A new clinical problem:
– first clinically significant VISA reported in Japan in 1996
– first clinically significant VRSA reported in USA in 2002
• Remains a very rare phenomenon
• VISA and VRSA have different resistance mechanisms
• Resistance is associated with a global increase
in the use of vancomycin. HOWEVER in ~50% of
cases, patients have not received prior therapy
with vancomycin
Antimicrobial features of VISA
• Mechanism not fully understood, but a combination of:
– increased quantities of PBPs causing extracellular trapping
– altered cell wall proteins reducing permeability
• Cross-resistance between vancomycin and teicoplanin
• Laboratory detection requires care
• Cross-resistance common with other agents,
particularly methicillin
Antimicrobial features of VRSA
• Mechanism due to acquisition by conjugative process
of vanA from enterococci
• Cross-resistance between vancomycin and teicoplanin
• Laboratory detection requires care
• Cross-resistance common with other agents,
particularly methicillin
Clinical features of VISA and VRSA
• Common associations are:
– underlying chronic diseases
– prolonged exposure to antibiotics
– detection during vancomycin treatment of
methicillin-resistant S. aureus
• No specific association with ICUs
• VISA and VRSA fail to respond to
glycopeptide therapy
• Usually susceptible to a range of other antibiotics
• Transmission to other patients or staff very rare
VISA and VRSA: infection control
• Control measures are as follows:
– ensure appropriate use of vancomycin
– educate on the risks and control measures
– adhere to strict control measures to prevent transmission,
particularly through contact
– conduct surveillance for the emergence of VISA and VRSA
Features of quinolone resistance
• There has been widespread use of quinolones:
– first introduced in 1980s for treatment of Gram-negative
bacteria
– newer-generation agents have a broader spectrum
of activity, including Gram-positive bacteria
• Resistance is growing in nosocomial infections
– susceptibility of Gram-negative isolates to ciprofloxacin
decreased from 86% (1994) to 76% (2000) in ICU patients
(US data)
– non-ICU patients also affected
Fridkin et al. Emerg Infect Dis 2002;8:697–701
Neuhauser et al. JAMA 2003;289:885–888
Features of quinolone resistance:
Gram-negative organisms
• Resistance most common in organisms associated with
nosocomial infections
– Pseudomonas aeruginosa
– Acinetobacter spp.
– also increasing among ESBL-producing strains
• Meropenem Yearly Susceptibility Test Information Collection
(MYSTIC) surveillance programme (1997―2000)
– 13.4% of Gram-negative strains resistant to ciprofloxacin
– P. aeruginosa and Acinetobacter baumannii are the most prevalent
resistant strains
– increasing prevalence of resistance during surveillance period
Masterton. J Antimicrob Chemother 2002;49:218–220
Thomson. J Antimicrob Chemother 1999;43(Suppl. A):31–40
Gram-negative organisms with resistance to
ciprofloxacin (1997 SENTRY data)
Organisms (%)
50
All patients (USA)
Lower RTI (USA and Canada)
40
30
20
10
0
Acinetobacter spp. P. aeruginosa Stenotrophomonas Escherichia
maltophilia
coli
Organism type
Jones. Chest 2001;119:397S–404S
Features of quinolone resistance:
Gram-positive organisms
• MRSA
– S. aureus occurred in 22.9% of pneumonias in hospitalised
patients in USA and Canada (1997 SENTRY data)
• Enterococcus spp. resistance
– has developed rapidly, especially among VRE
• Streptococcus pneumoniae resistance
– emerging in many countries, including
community-acquired resistance
– Hong Kong (12.1%), Spain (5.3%) and USA (<1%)
– marked cross-resistance with other
frequently used antibiotics
Hooper. Lancet Infect Dis 2002;2:530–538
Antimicrobial features of quinolone
resistance: gene mutation
• Stepwise chromosomal mutations leading to altered
target sites of enzymes
– DNA gyrase — commonly via GyrA subunit
– topoisomerase IV — commonly via ParC subunit
• Mutations occur in critical regions of enzyme–DNA
complex (‘quinolone resistance determining region’)
– quinolone affinity for target is reduced
– single amino acid mutations may be sufficient to confer
clinical resistance
– additional mutations usually required for resistance against
more potent quinolones
Schmitz et al. Eur J Clin Microbiol Infect Dis 2002;21:647–659
Antimicrobial features of quinolone
resistance: altered uptake
• Decreased membrane permeability
– new porin channels prevent entry of quinolone
into organism
• Multidrug efflux pump
– drug entering organism is actively pumped back out by
native pump in bacterial membrane
• Mechanisms of resistance
– vary, depending on quinolone and species of organism
– may occur alone or in combination
– must occur in combination for high-level resistance
Clinical features of quinolone resistance
• Spread by:
– quinolone exposure, which selects spontaneous mutants
– transmission of resistant clones in the healthcare setting,
especially in ICUs
• Resistance to one quinolone:
– reduces susceptibility to others
– increases the frequency of resistance development
Clinical implications of quinolone
resistance
Empiric monotherapy can no longer assure treatment
success for common nosocomial pathogens
Newer, more potent quinolones are unlikely to be clinically
useful given high resistance rates in MRSA and VRE
Fully resistant strains tend to have multidrug resistance to
other classes of antibiotic, leading to treatment failure
Hooper. Lancet Infect Dis 2002;2:530–538
Jones & Pfaller. Diagn Microbiol Infect Dis 1998;31:379–388
Management of quinolone resistance
• Continued overuse of quinolones
– promotes spread and selection of resistance
– limits their effectiveness
• Important steps are to
– avoid unnecessary use of quinolones
– administer at appropriate doses
• Careful adherence to infection-control practices
slows emergence and reduces transmission of
resistant strains
Features of carbapenem resistance (1)
• Carbapenems first introduced in late 1980s
– meropenem
– imipenem
• Excellent activity against most clinically significant
Gram-negative and Gram-positive bacteria
• Often used to treat serious nosocomial Gram-negative
infections that are resistant to traditional antibiotics
– stable to most prevalent -lactamases (ESBL, AmpC)
– retain excellent activity against many organisms
Features of carbapenem resistance (2)
• MYSTIC surveillance data
– most bacterial isolates worldwide remain susceptible
to carbapenems
• Gram-negative isolates from European ICUs have high
susceptibility rates
– 98.2–99.8% for meropenem
– 88.8–99.4% for imipenem
• Naturally occurring resistance seen in some organisms
– eg S. maltophilia
García-Rodríguez et al. J Chemother 2002;14:25–32
Turner. J Antimicrob Chemother 2000;46:9–23
Features of carbapenem resistance (3)
• Acquired resistance rare but becoming more common
– associated with increased use of carbapenems
• First reported in 1990s, particularly among:
– P. aeruginosa
– A. baumannii
– occasionally seen in Enterobacteriaceae spp.
• Resistance burden has been slow to increase
– compared with other classes of antibiotics
– even in presence of carbapenem use
Harris et al. Clin Infect Dis 2002;34:340–345
Jones. Chest 2001;119:397S–404S
Lepper et al. Antimicrob Agents Chemother 2002;46:2920–2925
Antimicrobial features of carbapenem
resistance
• Natural resistance is chromosomally mediated
– naturally occurring carbapenemases
• Acquired resistance is plasmid-mediated, involving
various mechanisms
– most commonly by carbapenemases (especially in
Gram-negative bacteria)
– reduced affinity of target PBPs
– decreased membrane permeability (Gram-negative
bacteria)
– active efflux pumps
• Mechanisms can co-exist and vary by pathogen
Antimicrobial features of carbapenem
resistance: carbapenemases
• Carbapenemases are a major source of acquired
resistance in Gram-negative bacteria
• Belong to three different molecular classes of
-lactamases:
– class B metallo-enzymes (eg IMP, VIM) — most clinically
significant
– class D oxacillinases (OXA-23 to OXA-27)
– class A clavulanic acid-inhibited enzymes (eg SME, NMC,
IMI, KPC) — most rare
Livermore & Woodford. Curr Opin Microbiol 2000;3:489–495
Antimicrobial features of carbapenem
resistance: cross-resistance
• Within-class cross-resistance is not absolute
– imipenem–meropenem cross-resistance only 5.9%
in a study of P. aeruginosa isolates
• Carbapenemases also hydrolyse penicillins;
hence, between-class cross-resistance is common:
– -lactams
– quinolones
– aminoglycosides
Livermore. Curr Opin Investig Drugs 2002;3:218–224
Mokaddas & Sanyal. J Chemother 1999;11:93–96
Clinical features of carbapenem
resistance: risk factors for resistance
• Nosocomial recovery of imipenem-resistant
P. aeruginosa
Risk factor
Antibiotic used:
Imipenem
Vancomycin
Piperacillin/tazobactam
Aminoglycoside
Intensive care unit
Time at risk
Odds ratio (95% CI)
p-value
4.96 (2.88–8.57)
1.80 (1.09–2.96)
2.39 (1.42–4.03)
2.19 (1.35–3.56)
3.26 (1.82–5.87)
1.02 (1.01–1.04)
<0.0001
0.02
0.0011
0.0015
<0.0001
0.0006
Multivariate analysis (n=120)
Harris et al. Clin Infect Dis 2002;34:340–345
Clinical features of carbapenem
resistance: risk factors for susceptibility
• Nosocomial recovery of imipenem-susceptible
P. aeruginosa
Risk factor
Antibiotic used:
Imipenem
Vancomycin
Ampicillin/sulbactam
Cephalosporin
Intensive care unit
Age
Odds ratio (95% CI)
p-value
0.37 (0.20–0.67)
1.64 (1.20–2.26)
2.00 (1.38–2.89)
2.00 (1.30–3.06)
3.53 (2.80–4.48)
1.02 (1.01–1.02)
0.0010
0.0022
0.0002
0.0015
<0.0001
<0.0001
Multivariate analysis (n=662)
Harris et al. Clin Infect Dis 2002;34:340–345
Clinical features of carbapenem
resistance
• Acquired resistance is most common with Pseudomonas spp.
and Acinetobacter spp. infections
• As resistance remains rare, carbapenems are probably drug of
choice in infections caused by Acinetobacter spp.
– carbapenem resistance is only 2.2% in isolates from routine clinical
samples collected in the UK
• However, nosocomial outbreaks have been recorded
– A. baumannii — major local outbreaks in several countries
– Klebsiella pneumoniae with multidrug resistance
Corbella et al. J Clin Microbiol 2000;38:4086–4095
Landeman et al. Arch Intern Med 2002;162:1515–1520
Manuel et al. J Antimicrob Chemother 2003;52:141–142
McKenzie et al. Lancet 1997;350:783; Poirel et al. J Clin Microbiol 2003;41:3542–3547
Management of carbapenem resistance
• Potential for greater resistance in the future,
especially:
– P. aeruginosa
– A. baumannii
– K. pneumoniae
• Promotes continued caution with carbapenem use
– particularly with availability of new oral and long half-life
forms
• Major cross-resistances mean that unusual therapy
may be required (eg polymixins, isepamicin,
minocycline, sulbactam)
Antibiotic resistance and inappropriate
antibiotic therapy
• Inappropriate antibiotic therapy can select for
antibiotic resistance
• Risk factors for antibiotic resistance and inappropriate therapy
include:
– prior antibiotic exposure
– prolonged length of hospital stay before treatment
– presence of invasive devices (eg intravascular or urinary catheters)
• Studies have been carried out that support the concept of using
appropriate antibiotic therapy in order to prevent or reduce the
incidence of antibiotic-resistant pathogens
Kollef. Clin Infect Dis 2000;31(Suppl. 4):S131–S138
Considerations for the selection of appropriate
antibiotic therapy in patients with VAP
Imipenem
+ amikacin + vancomycin
Ceftazidime
+ amikacin + vancomycin
Piperacillin–tazobactam
+ amikacin + vancomycin
Aztreonam
+ amikacin + vancomycin
0
Efficacy of combination therapy in critically
ill patients with VAP: choice based on local
data. All patients were ventilated 7 days
and had received prior antibiotic therapy
50
60
70
80
Susceptibility (%)
90
100
Trouillet et al. Am J Respir Crit Care Med 1998;157:531–539
Considerations for the selection of
appropriate antibiotic therapy in patients with
pulmonary infiltrates
• Overtreatment with antibiotics leads to higher rates of
antibiotic resistance and superinfections, while a shorter course
of therapy is appropriate in some patients and carries a lower
risk of resistance development
Antibiotic therapy
Short-course Control
Variable
(%)
(%)
p-value
Superinfection  resistance
MRSA
Candida spp.
P. aeruginosa
14
5
8
8
38
14
14
16
0.017
MRSA = methicillin-resistant Staphylococcus aureus
Singh et al. Am J Respir Crit Care Med 2000;162:505–511
Summary
• Antibiotic resistance in the hospital
setting is increasing at an alarming rate
and is likely to have an important impact on
infection management
• Steps must be taken now to control the
increase in antibiotic resistance
Cosgrove et al. Arch Intern Med 2002;162:185–190
Summary
• The Academy for Infection Management supports the
concept of using appropriate antibiotics early in
nosocomial infections and proposes:
– selecting the most appropriate antibiotic based on the patient,
risk factors, suspected infection and resistance
– administering antibiotics at the right dose for the
appropriate duration
– changing antibiotic dosage or therapy based on resistance and
pathogen information
– recognising that prior antimicrobial administration is a risk factor
for the presence of resistant pathogens
– knowing the unit’s antimicrobial resistance profile and choosing
antibiotics accordingly
Educational slide resource kit
Impact of inappropriate antibiotic treatment
on health economic outcomes
Pharmacoeconomic considerations in
antibiotic selection
• Pharmacoeconomic principles are used to
determine how to optimise patient outcomes for
a given limited supply of resources
• Selection of specific antibiotics for formulary
use requires analysis of all therapy-associated
costs and outcomes
Consideration of costs beyond just the
cost of the antibiotic is essential
Pharmacoeconomic considerations in
antibiotic selection
• Inappropriate antibiotic use can result in
treatment failure and development of resistance
• Economic implications of treatment failure
include costs associated with:
– increases in length of hospital stay
– additional treatments
– morbidity/adverse events
Relationship between antibiotic use, resistance,
treatment failure and healthcare burden
Increase in
antibiotic use
Limited treatment
alternatives
• more antibiotics
• increased
mortality
Increase in
resistant strains
Ineffective empiric
therapy
• increased morbidity
• more antibiotics
Increased
use of
healthcare
resources
Increased
hospitalisation
• more antibiotics
Decision tree to compare costs, choices
and outcomes between agents
Drug A
$13 200; 5.6 days
Drug B
$15 800; 6.6 days
Cure
p-Cure
[0.9]
$12 000 5.2 days
Fail
$24 000 9.8 days
1-(p-Cure)
[0.3]
Cure
p-Cure
[0.7]
$12 000 5.2 days
Fail
$24 000 9.8 days
1-(p-Cure)
[0.3]
Cost for each agent =
End cost x Probability (p) of achieving outcome
McKinnon et al. Clin Infect Dis 1997;24:57–63
Factors influencing choice of antibiotic
• Clinicians are influenced by a number of factors when
selecting an antibiotic:
– efficacy
– toxicity
– cost
• Antibiotic choice will depend on safety profiles if two
agents have comparable efficacy
• If both efficacy and safety profiles are roughly equal,
cost is usually the final factor considered
Total costs of antibiotic therapy
Total costs of therapy comprise:
• Costs associated with antibiotic preparation and
administration, ie all supplies and labour required to
deliver the dose to the patient
• Costs associated with any monitoring of the antibiotic necessary
for efficacy/tolerability evaluations (including supplies and labour
for ordering and attaining appropriate drug levels, reporting and
analysis of results and clinical interpretation)
• Costs of treatment outcome including:
– additional treatment costs and extended hospital stays due to
treatment failure
– costs associated with adverse outcomes (eg side effects,
allergy/hypersensitivity, intolerance to route of administration,
superinfection)
Evaluating costs of patient hospital stay
• Distinguish between costs attributable to the treatment
of infection and those attributable to another cause
• ‘Antibiotic-/infection-related length of stay’ should
include the numbers of days in hospital for:
– primary antibiotic therapy
– treatment of failures
– treatment of antibiotic-related adverse events
• Distinguish between days spent in the ICU vs non-ICU
days (due to high costs of ICU treatment)
Antibiotic strategies to reduce costs
Therapeutic failure Optimise PK/PD parameters; use potent bactericidal
agents; avoid antibiotics with poor tissue penetration
Hospital stay
Use knowledge of local resistance to initiate early therapy
with appropriate spectrum agent; IV vs PO
Administration
Use as short a course as appropriate; use IV–PO
switch programmes
Adverse events
Avoid agents with serious or costly adverse events;
avoid agents known to induce resistance
Monitoring
Avoid drugs requiring monitoring or laboratory
safety testing
Drug cost
Low impact compared to total hospital costs, but significant
to departmental cost (pharmacy)
Summary
• Hospital stay is often the biggest component of
infection-related treatment costs, therefore strategies
to treat infections effectively while minimising use of
hospital resources will have the greatest potential to
reduce overall cost of treatment
• To minimise the cost burden in nosocomial infections it
is very important to start with the appropriate empiric
antibiotic first