Transcript What is a complicated infection?

Managing the complicated
in cIAI and cSSTI
Professor Mark Wilcox
Head of Medical Microbiology
Clinical Director of Pathology
Leeds Teaching Hospitals & University of Leeds, UK
Lead on Clostridium difficile infection
Health Protection Agency
What is a complicated infection?
• May be very obvious, even to the naked eye
– e.g. infection complicating multiple abdominal
trauma or previous surgery
• May require a high index of suspicion
– e.g. early warning signs of necrotising fasciitis
• Almost always, requires risk factor assessment
What is a complicated infection?
• May be very obvious, even to the naked eye
– e.g. infection complicating multiple abdominal
trauma
• May require a high index of suspicion
– e.g. early warning signs of necrotising fasciitis
• Almost always, requires risk factor assessment
What constitutes a cSSSI?
• An SSTI is defined as ‘complicated’:
– when the infection involves the deeper skin structures, such as
fascia or muscle layers
– when the infection requires significant surgical intervention
– if the patient has a co-morbid condition resulting in a compromised
immune system
– if the infection occurs in areas at risk of Gram-negative or anaerobic
pathogen involvement
cSSTIs usually require hospitalisation,
intravenous antibiotics, and/or surgery
cSSTI, complicated skin and soft tissue infection
Sawyer et al 2008
What constitutes a cIAI?
• Uncomplicated IAIs involve a single organ and no
anatomical disruption is present, requiring only antimicrobial
therapy and occasionally immediate or deferred surgery
• An IAI is defined as ‘complicated’ when the infection extends
beyond the hollow viscus of origin into the peritoneal space
• cIAIs are associated with abscess formation or with
peritonitis
• cIAIs require either operative or percutaneous intervention
to resolve
cIAI, complicated intra-abdominal infection
Solomkin et al 2003
SSTIs can be considered as complicated
in the presence of co-morbidities
Diabetes mellitus
Organ transplantation
Chronic renal failure
HIV infection
Chronic steroid use
Immunosuppression
Advanced age
Malnourishment
Bacteremia
Cellulitis >3% BSA
Steroids >7.5 mg
Neutropenia
Cirrhosis
Burn injury
Radiation therapy
Alcoholism
Chronic immunosuppressive
therapy
BSA, body surface area
SSTIs can be considered as complicated
in the presence of co-morbidities
Diabetes mellitus
Organ transplantation
Chronic renal failure
HIV infection
Chronic steroid use
Immunosuppression
Advanced age
Malnourishment
Bacteremia
Cellulitis >3% BSA
Steroids >7.5 mg
Neutropenia
Cirrhosis
Burn injury
Radiation therapy
Alcoholism
Chronic immunosuppressive
therapy
BSA, body surface area
Risk factors for the acquisition
of MDR pathogens
Prior exposure to antibiotics
Severity of infection
Compromised immunity
Length of hospitalisation
Underlying disease
Healthcare-associated
infection
Patient age
Graffunder & Venezia 2002; Graffunder et al 2005
The ‘complicated’ dilemma for the local
antibiotic prescriber
• How best to choose appropriate antibiotic
therapy for patients with complicated infection?
– Large number of antibiotics that have been used
for complicated infections
– Clear simple guidance on the optimum choice in
such patients is unrealistic
– Instead, patient-centred, risk-benefit approach
to antibiotic choice is needed
The ‘complicated’ dilemma for the local
antibiotic prescriber
• How best to choose appropriate antibiotic
therapy for patients with complicated infection?
– Choice is further complicated by the risk of
antibiotic resistance and the risk of selection of
antibiotic resistance
– Put simply, the optimal choice is influenced by
what is best for the current patient ?
and
what is best for the next patient ?
The whole picture…
Spectrum of activity
of broad-spectrum agents
Resistant
Grampositive
Grampositive
Gramnegative
Resistant
Gramnegative
ANO2
Atypical
Pseudo
Carbapenem*
Piperacillin/
tazobactam
3GC
Quinolone
Tigecycline**
////
*Excludes ertapenem, which has no Pseudomonas coverage
**Although tigecycline has demonstrated in vitro activity against atypicals, these organisms
are not implicated in cIAI and cSSTI, the two current licensed indications for tigecycline
Wyeth GMA Literature Review
Selection risks associated with
major antimicrobial classes
MRSA
VRE
ESBL
MDR
pseudo
C. difficile
Carbapenems
Piperacillin/
tazobactam
3GC
Fluoroquinolones
Cao B et al. J Hosp Infect 2004;57:112-18; Gerding DN. Clin Infect Dis 1997;25(Suppl 2):S206-10;
Padiglione AA et al. Antimicrob Agents Chemother 2003;47:2492-8;
Carsenti-Etesse H et al. Clin Microbiol Infect 2001;7:144-51;
Paterson DL. Clin Infect Dis 2004;38(Suppl 4):S341-5. Carmeli Y et al. Emerg Infect Dis 2002;8:802-7
Selection risks associated with
major antimicrobial classes
MRSA
VRE
ESBL
MDR
pseudo
C. difficile
Carbape
nemases
?
Carbapenems
Piperacillin/
tazobactam
3GC
Fluoroquinolones
Cao B et al. J Hosp Infect 2004;57:112-18; Gerding DN. Clin Infect Dis 1997;25(Suppl 2):S206-10;
Padiglione AA et al. Antimicrob Agents Chemother 2003;47:2492-8;
Carsenti-Etesse H et al. Clin Microbiol Infect 2001;7:144-51;
Paterson DL. Clin Infect Dis 2004;38(Suppl 4):S341-5. Carmeli Y et al. Emerg Infect Dis 2002;8:802-7
Antimicrobial drug use and MRSA
Aberdeen, UK, 1996-2000
Lag times
Macrolides
1-3 months
3rd-gen cephalosporins 4-7 months
Fluoroquinolones
4-5 months
MRSA prevalence
Sum of lagged macrolide, 3rd-generation cephalosporin
and fluoroquinolone consumption series
MRSA, methicillin-resistant Staphylococcus aureus
Monnet DL et al. Emerg Infect Dis 2004;10:1432-41
Resistance to ceftazidime in E. coli- and
Enterobacter spp.-causing bacteraemia
England, Wales and Northern Ireland, 1994-2007
E. coli
Enterobacter spp.
Health Protection Agency. Antimicrobial Resistance and Prescribing in England, Wales
and Northern Ireland, 2008. London: Health Protection Agency, July 2008
Risk factors for ESBL-producing isolates
Risk factor
Odds ratio
95% CI
p value
Treatment with 2GC
15.8
1.7-143.0
<0.0001
Treatment with 3GC
10.1
4.2-24.0
0.009
Hospitalisation in the past 3
months
8.95
3.7721.25
<0.0001
Treatment with quinolones
4.1
1.8-9.0
<0.0001
Treatment with penicillin
4.0
1.6-9.0
<0.0001
Antibiotics in the past 3 months
3.23
1.76-5.91
<0.0001
Age 60 years or older
2.65
1.45-4.83
<0.0001
Diabetes
2.57
1.20-5.51
<0.0001
Male gender
2.47
1.22-5.01
<0.0001
Infection with Klebsiella spp.
2.31
1.17-4.54
<0.0001
CI, confidence interval; 2GC, 2nd-generation cephalosporin;
3GC, 3rd-generation cephalosporin
Colodner R et al. Eur J Clin Microbiol Infect Dis 2004;23:163-7
Risk factors for ESBL-producing isolates
Risk factor
Odds ratio
95% CI
p value
Treatment with 2GC
15.8
1.7-143.0
<0.0001
Treatment with 3GC
10.1
4.2-24.0
0.009
Hospitalisation in the past 3
months
8.95
3.7721.25
<0.0001
Treatment with quinolones
4.1
1.8-9.0
<0.0001
Treatment with penicillin
4.0
1.6-9.0
<0.0001
Antibiotics in the past 3 months
3.23
1.76-5.91
<0.0001
Age 60 years or older
2.65
1.45-4.83
<0.0001
Diabetes
2.57
1.20-5.51
<0.0001
Male gender
2.47
1.22-5.01
<0.0001
Infection with Klebsiella spp.
2.31
1.17-4.54
<0.0001
CI, confidence interval; 2GC, 2nd-generation cephalosporin;
3GC, 3rd-generation cephalosporin
Colodner R et al. Eur J Clin Microbiol Infect Dis 2004;23:163-7
Evidence for the effectiveness of
antibiotic restriction
E. coli from blood & CSF
%
Resistant
25
20
Cipro
3 gen ceph
both
15
10
5
0
90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09
Supplied by D Livermore, HPA
Imipenem use and A. baumannii
DDD, defined daily doses
Reprinted from Corbella X et al. J Clin Microbiol 2000;38:4086-95
Mechanisms of carbapenem resistance in
Enterobacteriaceae
• Carbapenemase production
• Cephalosporinase (e.g. ESBL or AmpC-type
enzymes) + porin loss
Common carbapenemases
Enzyme
Bacteria
KPC
Enterobacteriaceae
Metallo-b-lactamase
P. aeruginosa
OXA
Acinetobacter spp.
SME
Serratia marcesens
NDM
Enterobacteriaceae
International dissemination of NDM-1
(up to 2010)
Data provided by D Livermore. Health Protection Agency, UK
Carbapenemases in Enterobacteriaceae
in UK (to 2011, n = 226)
Outbreak involving >2 patients @ one site
with UK transmission
Data provided by D Livermore. Health Protection Agency, UK
Carbapenemases in Enterobacteriaceae
in India (Hinduja Hospital, Mumbai - tertiary care centre)
• Sept 2009 - May 2010, 310 carbapenem-resistant Gramnegative bacilli were isolated from clinical samples
• Enterobacteriaceae (57), Pseudomonas species (173),
and Acinetobacter species (71)
• Incidence of carbapenem resistance in Enterobacteriaceae
– 5% in blood isolates
– 8% in respiratory tract isolates
– 5% in urine isolates
• 49/57 had NDM-1
– Klebsiella (28), E. coli (13), Enterobacter (5), M morganii (2)
& Citrobacter spp (1).
– All received carbapenems in previous month
Deshpande P. Clin Infect Dis 2010;51:1222..
Carbapenemases in Enterobacteriaceae
in India (Hinduja Hospital, Mumbai - tertiary care centre)
• Sept 2009 - May 2010, 310 carbapenem-resistant Gramnegative bacilli were isolated from clinical samples
• Enterobacteriaceae (57), Pseudomonas species (173),
and Acinetobacter species (71)
• Incidence of carbapenem resistance in Enterobacteriaceae
– 5% in blood isolates
– 8% in respiratory tract isolates
– 5% in urine isolates
• 49/57 had NDM-1
– Klebsiella (28), E. coli (13), Enterobacter (5), M morganii (2)
& Citrobacter spp (1).
– ALL received carbapenems in previous month
Deshpande P. Clin Infect Dis 2010;51:1222..
CRKP: Puerto Rico
Hospital-Acquired, Community-Onset, and Active Surveillance Cases
Jan 2006 - Sept 2008
9
8
7
6
5
4
3
Surveillance
Community-Onset
Hospital-Acquired
2
1
0
Preliminary findings, confidential
www.bt.cdc.gov/coca/ppt/CRE_031709_Patel_Srinivasan_CE.pps March 2009
Prior antibiotics
CRKP
(n=99)
CSKP
(n=99)
p value
Cephalosporins
63
31
<0.001
Fluoroquinolones
36
23
0.05
β-lactam / inhibitor
54
33
0.005
Aminoglycosides
14
3
0.01
Carbapenems
54*
6
<0.001
*48% on carbapenems at time of isolation of CRKP
69% either on carbapenems or completed a course of carbapenems
within 2 weeks prior to CRKP isolation
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-106
Mortality
60
p<0.001
Percent of subjects
50
p<0.001
40
CRKP
CSKP
30
20
10
48
20
38
12
0
Overall Mortality
Attributable
Mortality
OR 3.71 (1.97-7.01)
OR 4.5 (2.16-9.35)
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-106
Antibiotic susceptibility of
KPC-positive K. pneumoniae
Antimicrobial
Interpretation
Antimicrobial
Interpretation
Amikacin
I
Chloramphenicol
R
Amoxicillin/clavul
anate
R
Ciprofloxacin
R
Ampicillin
R
Ertapenem
R
Aztreonam
R
Gentamicin
R
Cefazolin
R
Imipenem
R
Cefpodoxime
R
Meropenem
R
Cefotaxime
R
Piperacillin/tazobac
tam
R
Cefotetan
R
Tobramycin
R
Cefoxitin
R
Trimethoprim/
sulfamethoxazole
R
Ceftazidime
R
Polymyxin B
MIC >4 μg/ml
Ceftriaxone
R
Colistin
MIC >4 μg/ml
Cefepime
R
Tigecycline
S
www.bt.cdc.gov/coca/ppt/CRE_031709_Patel_Srinivasan_CE.pps March 2009
Worldwide MDR ESKAPE1 pathogens
North America
VRE
33.4%
MRSA
53.7%
K. pneumoniae
9.7%
A. baumannii
13.1%
P. aeruginosa
15.1%
Enterobacter spp. 22.9%
Latin America
VRE
46.3%
MRSA
46.6%
K. pneumoniae
37.9%
A. baumannii
37.6%
P. aeruginosa
35.8%
Enterobacter spp. 43.4%
VRE, vancomycin-resistant Enterococci;
MRSA, methicillin-resistant Staphylococcus aureus
Europe
VRE
16.3%
MRSA
25.1%
K. pneumoniae
15.3%
A. baumannii
14.8%
P. aeruginosa
17.4%
Enterobacter spp. 25.6%
Asia-Pacific
VRE
22.5%
MRSA
40.7%
K. pneumoniae
19.7%
A. baumannii
32.6%
P. aeruginosa
18.1%
Enterobacter spp. 42.8%
Source: www.testsurveillance.com;
1Rice 2008
The prevalence of ESBLs
Asia-Pacific, 2007
100
Percent ESBL-positive
E. coli
K. pneumoniae
80
Klebsiella oxytoca
60
40
20
0
India
China
Thailand
Vietnam Singapore S. Korea
Hong
Kong
Hawser et al. AAC 2009
Philippines Taiwan
Australia
New Asia-Pacific
Zealand
overall
Carbapenem-resistant P. aeruginosa
(CRPA) and A. baumannii (CRAB) in Asia
Region
Taiwan1
Singapore2
Japan3,4
Mainland China5
Korea6-8
CRAB (%)
CRPA (%)
32.1
49.6
30.0
40.0
28.6
18.4
9.6
38
30
3-19
1Kuo
et al 2008; 2Hsu et al 2007;
et al 2008; 4Tsuchimochi et al 2008;
5Wang 2010 (personal communication); 7Perez et al 2007; 8Kim et al 1998
3Feizabadi
31 / 47 since 2008
Treatment failure & recurrence after
metronidazole treatment of CDI
Jung KS et al. Gut Liver 2010;4:332-7.
Antibiotics and risk of CDI
Need to minimise all antibiotic use: polypharmacy and duration
High risk
Medium risk
Low risk
Cephalosporins
Clindamycin
Ampicillin/amoxycillin
Co-trimoxazole
Macrolides
Fluoroquinolones
Aminoglycosides
Metronidazole
Anti-pseudomonal
penicillins +
β-lactamase inhibitors
Tetracyclines
Rifampicin
Vancomycin
Evidence to support
the restriction
of these as a control
measure for CDI
CDI may still occur!
Tigecycline and C. difficile
• Tigecycline is highly active (MIC=0.06 mg/L) against C. difficile
Baines SD et al. J Antimicrob Chemother 2006;58:1062-5
• No in vitro evidence of increased risk of tigecycline-induced CDI
Baines SD et al. J Antimicrob Chemother 2006;58:1062-5
• No in vivo evidence of increased risk of tigecycline-induced CDI
Wilcox MH. Clin Microbiol Infect 2007;13:949-52.
• Some evidence that tigecycline could be used to treat CDI
(THIS IS NOT A LICENSED INDICATION)
Herpers BL, et al. Clin Infect Dis 2009;48:1732-5.
Lu CL, et al. Int J Antimicrob Agents 2010;35:311-2.
Induction of C. difficile toxin production
Baines SD et al. J Antimicrob Chemother 2005;55:974-82;
Baines SD et al. J Antimicrob Chemother 2006;58:1062-5
Tigecycline and C. difficile
• Tigecycline is highly active (MIC=0.06 mg/L) against C. difficile
Baines SD et al. J Antimicrob Chemother 2006;58:1062-5
• No in vitro evidence of increased risk of tigecycline-induced CDI
Baines SD et al. J Antimicrob Chemother 2006;58:1062-5
• No in vivo evidence of increased risk of tigecycline-induced CDI
Wilcox MH. Clin Microbiol Infect 2007;13:949-52.
• Some evidence that tigecycline could be used to treat CDI
(THIS IS NOT A LICENSED INDICATION)
Herpers BL, et al. Clin Infect Dis 2009;48:1732-5.
Lu CL, et al. Int J Antimicrob Agents 2010;35:311-2.
HO-HCFA CDI associated with age, PPIs &
admission from skilled nursing facility
 Patients on proton pump
8%
inhibitors prior to the index
event had an increased risk of
HO-HCFA CDI
HO-HCFA CDI Rate
7%
6%
Odds Ratio: 1.61;
95% CI (1.34-1.93)
5%
4%
3%
 Patients admitted from a
2%
skilled nursing facility had an
increased risk for HO-HCFA
CDI
1%
0%
18-29
30-39
40-49
50-59
60-69
70-79 80-90+
Odds Ratio: 3.47;
95% CI (2.39-4.92)
Emons MF, et al. Risk factors associated with Clostridium difficile infection in hospitalized patients with
hospital-onset healthcare facility-associated Clostridium difficile infection. ECMMID 2010. Abstract O162.
Antibiotics received prior to index event
associated with HO-HCFA CDI
Odds Ratio; 95% CI
Total Number of Systemic Antibiotics
(by Drug Class) Referent = 0 or 1
2
1.54; (1.25-1.90)
≥3
1.82; (1.42-2.34)
Miscellaneous Antibiotics
2.59; (1.99-3.36)
Carbapenems
2.09; (1.38-3.18)
3rd/4th Gen. Cephalosporins
1.64; (1.45-1.86)
Tigecycline
0.21; (0.06-0.76)
Emons MF, et al. Risk factors associated with Clostridium difficile infection in hospitalized patients with
hospital-onset healthcare facility-associated Clostridium difficile infection. ECMMID 2010. Abstract O162.
Antibiotics received prior to index event
associated with HO-HCFA CDI
Odds Ratio; 95% CI
Total Number of Systemic Antibiotics
(by Drug Class) Referent = 0 or 1
2
1.54; (1.25-1.90)
≥3
1.82; (1.42-2.34)
Miscellaneous Antibiotics
2.59; (1.99-3.36)
Carbapenems
2.09; (1.38-3.18)
3rd/4th Gen. Cephalosporins
1.64; (1.45-1.86)
Tigecycline
0.21; (0.06-0.76)
Emons MF, et al. Risk factors associated with Clostridium difficile infection in hospitalized patients with
hospital-onset healthcare facility-associated Clostridium difficile infection. ECMMID 2010. Abstract O162.
SIS and IDSA consensus
guidelines for cIAI (2010)
Source control
is important
Rapid
intravascular
resuscitation
advised
Guiding
principles
Gram staining and
culture for HCA /
hospital-acquired
cIAIs only
SIS, Surgical Infection Society; IDSA, Infectious Diseases Society of America;
HCA, healthcare-associated
Immediate
administration
of appropriate
antibiotics
Immediate
plating of
anaerobic
cultures is vital
Solomkin et al. CID 2010
Solomkin et al. CID 2010
Solomkin et al. CID 2010
Tigecycline and MDR
Enterobacteriaceae
• Systematic review: microbiological activity and clinical
effectiveness of tigecycline for multidrug-resistant (MDR)
Enterobacteriaceae
• 26 microbiological & 10 clinical studies were identified
• FDA (MIC <2 mg/L) or EUCAST (<1 mg/L) breakpoints
Kelesidis T et al. J Antimicrob Chemother 2008;62:895-904.
Kelesidis T et al. J Antimicrob Chemother 2008;62:895-904.
Tigecycline and MDR
Enterobacteriaceae
• In clinical studies, 69.7% of the 33 reported patients
treated with tigecycline achieved resolution of an
infection caused by a carbapenem-resistant or ESBLproducing or MDR Enterobacteriaceae
Kelesidis T et al. J Antimicrob Chemother 2008;62:895-904.
Antimicrobial
stewardship
The antibiotic prescribing bundle
• Use monotherapy whenever possible for initial
(empiric) treatment
• Optimise dose and duration
• Perform a regular risk assessment
– For each patient
– Impact of the programme
Adapted from Wisplinghoff et al. CID 2004: 39
Empiric choice Empiric choice
Cephalosporins
[Cef / Met
prophylaxis]
Aminoglycosides
2nd / 3rd line
Final option
BLICs
Glycopeptides
Monotherapy
Tigecycline
or
combination?
Carbapenems
Oxazolidinones
Lipopeptides
Fluoroquinolones
Low resistance
risk and
minimal
complexity
Increased
resistance risk
and
complexity
Treatment failure
Implicated in CDI / MRSA selection
Used as Gram-positive agent
Patient history at admission
•
•
•
58-year-old policeman
Experienced liver / abdominal
pain after eating a burger and
smoking a cigarette during
observation of a suspect
Self-prescribed paracetamol
•
•
•
•
•
•
Nausea
Vomiting (3x)
Fever 38.2°C
Abdominal pain,
right upper quadrant
No diarrhoea
After duty, presented to the
emergency room
Patient management
Gallbladder removed for cholecystitis with stones
No abscesses, empirical cefuroxime given
Surgical wound developed a pus-producing infection
Sepsis and organ failure
Further surgery
cSSTI case study: patient history
44-year-old man with a history of Alport
syndrome, ESRD (CRT in 1985), deafness, and
recurrent squamous cell. Remains on
tacrolimus therapy
Chief complaint: right thigh abscess after
recent
right superficial groin dissection; treated with
cephalexin (oral) without response x 5 days
Medical history: as above plus >80 squamouscell carcinomas and >40 episodes of cellulitis
after excision treated with various antibiotics
ESRD, end-stage renal disease
CRT, cadaveric renal transplant
cSSTI case study:
investigations and examinations
Allergies: no drug allergies
Vitals: T 101.3oC, HR 98 bpm, BP 120/70 mm/Hg,
respiratory rate 14
Physical exam: tense right thigh abscess over prior
suture line (skin closed) 7 x 8 cm, skin warm, markedly
erythematous
Laboratory results: WBC 12.7K cells/µl, 75% PMN,
20 bands. Electrolytes and LFTs normal. BUN 48,
creatinine 3.9 down from 5.7; 2 weeks in chronic
rejection
PMN, polymorphonuclear leukocyte
cSSTI case study
Cultures grew ESBL-producing
E. coli and MRSA
Started on tigecycline
monotherapy and treated
for 10 days
Received 4 days of tigecycline in
hospital and the rest as an
outpatient. Wound recovered
without further surgical Rx
Antibiotic choice in
complicated infection / patients
• Capacity to cover resistant pathogens
• Proven efficacy in MDR infection
• Pharmacokinetic and pharmacodynamic profile
• Safety profile
• Low potential for inducible resistance
• Capacity not to select for resistant pathogens
• Capacity not to induce ‘overgrowth’, eg CDI
MDR, multi-drug-resistant; CDI, Clostridium difficile infection
Antibiotic choice in
complicated infection / patients
• Should consider measures to reduce use of 3rd
gen cephs, fluoroquinolones & carbapenems
• Monotherapy has practical and theoretical
advantages
• Increased reliance on carbapenems may
accelerate emergence of completely resistant
isolates
• Consider this patient and the next patient
Choose wisely
Other Notable Risk Factors Associated
with HO-HCFA CDI
• Patients on proton pump inhibitors prior to the index
event had an increased risk of HO-HCFA CDI
Odds Ratio: 1.61; 95% CI (1.34-1.93)
• Patients admitted from a skilled nursing facility had an
increased risk for HO-HCFA CDI
Odds Ratio: 3.47; 95% CI (2.39-4.92)
Emons MF, et al. Risk factors associated with Clostridium difficile infection in hospitalized patients with
hospital-onset healthcare facility-associated Clostridium difficile infection. ECMMID 2010. Abstract O162.
Significance of bacteria producing
NDM-1 carbapenemase
• Carbapenems ‘last resort’ drugs vs. multi-resistant
bacteria
• Carbapenemases destroy carbapenems
• Very rare in Enterobacteriaceae until 2008, then
– Import of KPC & VIM types from Greece, Israel
•
•
•
•
– ‘Unknown enzyme’ first producer Aug 2008
Proved to be NDM-1: first found in Swedish patient, just
returned from New Delhi in Jan 2008
More cases during 2008-9
Usually susceptible to only 2 drugs (tigecycline & colistin)
Resistance alerts to UK labs: Jan & July 2009
Carbapenemases in Enterobacteriaceae
in UK (Lancet Infect Dis 2010)
• 29 UK cases; mixed species, strains
• 17 prior travel to Indian subcontinent
• 12 prior hospitalisation there
• Wide distribution in India & Pakistan
• Prevalence uncertain
• Resistance transferring among species
Data provided by D Livermore. Health Protection Agency, UK
Multivariate risk-factor analysis for
imipenem-resistant A. baumannii
Variable
Age
1.03 (1.01-1.05)
Time at risk
1.02 (1.002-1.03)
ICU stay
21.54 (10.73-43.23)
Imipenem
9.18 (3.99-21.13)
3GC
OR, odds ratio
OR (95% CI)
2.11 (1.13-3.95)
Lee SO et al. Antimicrob Agents Chemother 2004;48:224-8
Multivariate risk-factor analysis for
imipenem-resistant A. baumannii
Variable
OR (95% CI)
Age
1.03 (1.01-1.05)
Time at risk
1.02 (1.002-1.03)
ICU stay
21.54 (10.73-43.23)
Imipenem
9.18 (3.99-21.13)
3GC
2.11 (1.13-3.95)
Lee SO et al. Antimicrob Agents Chemother 2004;48:224-8
Resistance to ciprofloxacin in E. coliand Klebsiella spp.-causing bacteraemia
England, Wales and Northern Ireland, 1994-2007
E. coli
Klebsiella spp.
Health Protection Agency. Antimicrobial Resistance and Prescribing in England, Wales
and Northern Ireland, 2008. London: Health Protection Agency, July 2008
EARSS 2007: resistance and co-resistance in
invasive Klebsiella pneumoniae (n= 10,046)
Resistance results only shown for 3 antibiotic classes
*Reporting of carbapenems susceptibility was not obligatory within EARSS in 2007
EARSS, European Antimicrobial Resistance Surveillance System
Tigecycline for MDR A. baumannii
Metan G, et al. Clinical experience with
tigecycline in the treatment of carbapenemresistant Acinetobacter infections. J
Chemother. 2010 Apr;22(2):110-4.
Gordon NC, Wareham DW. A review of
clinical and microbiological outcomes
following treatment of infections involving
multidrug-resistant Acinetobacter
baumannii with tigecycline. J Antimicrob
Chemother. 2009 Apr;63(4):775-80.
Curcio D, et al. Tigecycline in the treatment
of Ventilator-Associated Pneumonia:
experience from the Latin American
Tigecycline Use Registry. Infez Med. 2010
Mar;18(1):27-34.
Tigecycline for MDR A. baumannii
• Retrospective study of patients who received tigecycline for
tige-S carbapenem-R Acb-complex infections 2008-09
• 21 patients (median age 48 years), median duration tige 14 d
• 18 patients were treated with tigecycline as the sole pathogen
• Most common indication for tigecycline was SSI (VAP)
• Tigecycline was the sole antibiotic in 7 patients
• 2 patients died within 14 days, 4 died within 30 days
• 17/21 ‘had successful clinical outcomes’ BUT 14/21 had
microbiological failure
• Poor correlation between micro and clinical response
• Clinical failure was more common in patients with VAP
• Patients with bacteraemia or VAP more likely to have
microbiological failure
Metan G et al. J Chemother 2010;22:110-4.
Colistin for MDR A. baumannii
• 166 consecutive patients infected or colonised with
carbapenem- and MDR A. Baumannii
• 18 hospitals (London, UK); 141 belonged to OXA-23 clone 1
• Only colistin and tigecycline retained good in vitro activity,
with 99.4% and 81.9% of isolates susceptible, respectively,
• 62% patients in ICU or HDU, 84 (50.6%) infected
• Survival rates among infected and colonised patients were
68% and 67%, indicating little attributable mortality
Livermore D et al. Int J Antimicrob Agents 2010;35:19-24.
Colistin for MDR A. baumannii
• Univariate and multivariate analyses:
– poorer outcomes among ICU-infected patients, pulmonary
infection or bacteraemia
– trauma patients had significantly better outcome
• Outcomes varied by hospital (multivariate analysis) CASE MIX
• Poor association between outcome and therapy with colistin
(and/or tigecycline)
• Patients with respiratory infection, 12/15 treated with
intravenous colistin alone had poor outcome compared with
1/8 whose therapy include nebulised colistin (P=0.003)
BUT, the patients receiving nebulised drug were mostly
younger, included trauma cases and were at a hospital
with good outcomes
Livermore D et al. Int J Antimicrob Agents 2010;35:19-24.
Risk factors for and outcomes
of CRKP infections
• Case control study by Patel et al at Mount Sinai in
New York City, where CRKP is now endemic
– 99 patients with invasive CRKP infections
Compared with
– 99 patients with invasive CSKP infections
CSKP, carbapenem-susceptible K. pneumoniae
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-106
Pre-infection LOS and risk factors
Pre-infection
LOS
Mean
Median
CRKP
(n=99)
CSKP
(n=99)
25.1 ± 25
6.44 ± 10
21
1
0-129
0-59
p value
<0.001
Range
Antibiotics, co-morbidities, ventilation, central venous catheter
LOS, length of stay
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-106
Isolates producing NDM-1 were disseminated
in Indian health care facilities as early as 2006
• Among 39 carbapenem-resistant Enterobacteriaceae
isolated in 2006-07 in India
– 15 strains carried bla(NDM-1)
– 10 harboured a gene encoding a variant of the
carbapenemase OXA-48, named bla(OXA-181)
– 1 E. cloacae strain possessed bla(VIM-6)
– 1 K. pneumoniae strain carrying bla(OXA-181) also
possessed bla(VIM-5)
– Multiple pulsed-field gel electrophoresis patterns
and clonal dissemination within and among sites
were observed
Castanheira M. et al. Antimicrob Agents Chemother 2011;55:1274-8.
Isolates producing NDM-1 were disseminated
in Indian health care facilities as early as 2006
• Among 39 carbapenem-resistant Enterobacteriaceae
isolated in 2006-07 in India
– 15 strains carried bla(NDM-1)
– 10 harboured a gene encoding a variant of the
carbapenemase OXA-48, named bla(OXA-181)
– 1 E. cloacae strain possessed bla(VIM-6)
– 1 K. pneumoniae strain carrying bla(OXA-181) also
possessed bla(VIM-5)
– Multiple pulsed-field gel electrophoresis patterns
and clonal dissemination within and among sites
were observed
Castanheira M. et al. Antimicrob Agents Chemother 2011;55:1274-8.
Tigecycline in ICU setting
% with
60
indication
n=70
Microorganism
cIAI
Infections, n (%)
Enterococcus faecium
26 (37)
VRE
15 (21)
Strenotrophomonas maltophilia
13 (19)
Infection of unknown origin
11 (16)
Enterococcus faecalis
7 (10)
MRSA
4 (6)
20
Enterococci, species
not determined
4 (6)
10
Acinetobacter baumannii
1 (1)
Burkholderia cepacia
1 (1)
Enterococcus casseliflavus or Enterococcus
gallinarum
1 (1)
50
cSSTI
Mixed
40
30
0
Other
•
APACHE II scores 27 ± 10, SOFA 12 ± 3
Enterobacter cloacae
1 (1)
•
Overall mortality 30%
Enterococcus durans
1 (1)
APACHE, Acute Physiology and Chronic Health Evaluation;
SOFA, Sequential Organ Failure Assessment
Swoboda et al. J Antimicrob Chemother 2008
Tigecycline in ICU setting
• Mean duration of tigecycline therapy = 9 (+/- 4) days
• 76% patients received tigecycline in combination (64%
second line)
• APACHE score & renal replacement were predictive
factors for mortality
Swoboda et al. J Antimicrob Chemother 2008
Tigecycline in ICU setting
• Mean duration of tigecycline therapy = 9 (+/- 4) days
• 76% patients received tigecycline in combination (64%
second line)
• APACHE score & renal replacement were predictive
factors for mortality
• AUTHOR CONCLUSIONS:
‘Tigecycline treatment of critically ill SICU patients with
severe sepsis or septic shock appeared to result in
remarkably low mortality.
Tigecycline may be an important treatment option for
septic patients with infections resistant to other
available agents.’
Swoboda et al. J Antimicrob Chemother 2008
Antibiotic choice in high-risk patients
• Capacity to cover resistant pathogens
• Proven efficacy in MDR infection
• Pharmacokinetic and pharmacodynamic profile
• Safety profile
• Capacity not to induce ‘overgrowth’, eg CDI
• Low potential for inducible resistance
• Capacity not to select for resistant pathogens
MDR, multi-drug-resistant; CDI, Clostridium difficile infection
Treatment & antimicrobial
resistance
• High-risk patients
• Modifiable risk factors
• Evidence that antibiotic control does work
• The way forward
Antibiotic resistance is inevitable
The rate of spread of resistance
is not inevitable
Selection of antimicrobial resistance
Use of antimicrobials
Prudent use
Overuse/misuse
Selection of resistant bacteria

Once established, resistance is not always reversible

There is a continuing need for new antimicrobial agents
active against resistant pathogens
Antibiotic pipeline
• The approval of new antibiotics decreased by
almost 60% comparing the periods 1998-2002
and 1983-1987
• Since 1998 the FDA has approved only 10 ‘new’
antibacterial agents
• Of these, only three actually had novel
mechanisms of action
• New antibiotics constitute only 5 of more than 500
drugs disclosed in the developmental programs of
the largest pharmaceutical and biotechnology
companies
Adapted from Wisplinghoff et al. CID 2004: 39
selection of resistance ...
… is simply Darwinian selection
“the sensitive die, the resistant survive”
Microbial multiplication
medically important microbes
• Virus
More than 1 billion HIV infected white blood cells are
infected and destroyed daily
• Bacterium
E. coli double every 20 minutes (1 million overnight)
• Fungus
Candida has slower replication (~2-3 hours)
• Protozoan
Malaria parasites complex replication and release
Emergence of antimicrobial
resistance
Susceptible Bacteria
Resistant Bacteria
Resistance Gene Transfer
New Resistant Bacteria
Resistant Strains
Rare
Antimicrobial
Exposure
Resistant Strains
Dominant
Patient history at admission
•
•
•
58-year-old policeman
Experienced liver / abdominal
pain after eating a burger and
smoking a cigarette during
observation of a suspect
Self-prescribed paracetamol
•
•
•
•
•
•
Nausea
Vomiting (3x)
Fever 38.2°C
Abdominal pain,
right upper quadrant
No diarrhoea
After duty, presented to the
emergency room
Patient management
Gallbladder removed for cholecystitis with stones
No abscesses, empirical cefuroxime given
Surgical wound developed a pus-producing infection
Sepsis and organ failure
Further surgery
cIAI case study: patient history
58-year-old woman admitted with severe gallstone pancreatitis
Past medical history: hypertension, diabetes mellitus, hypercholesterolemia,
mild aortic stenosis, depression
Past surgical history: subtotal gastrectomy for bleeding duodenal ulcer, appendectomy
Medications: metoprolol, insulin, atorvastatin, venlafaxine
Allergies: penicillin, sulfamethoxazole, vancomycin
Physical exam: extremely ill, appearing in distress
Heart: aortic stenosis murmur, tachycardia
Chest: decreased bilaterally, tachypnea
Abdomen: distended, tympanitic, marked mid-epigastric tenderness, no rebound
cIAI case study: patient management
Initial CT: severe pancreatitis with phlegmon
throughout the entire gland, minimal ascites,
and gallstones
Patient condition worsens over the next
24 hours and she is intubated
She stabilizes over the next 72 hours;
TPN is started and she is slowly weaned
HD #6, T 39.1oC, BP 120/80 mm/Hg, HR 88 bpm
Repeat CT demonstrates substantial air
in the retro peritoneum
CT, computed tomography; TPN, total parental nutrition;
HD, hospital day ; T, temperature; BP, blood pressure; HR, heart rate
cIAI case study: patient deteriorates
Patient condition fails to improve over 6 days
WBC rises to 30,000 cells/µl, so she undergoes a pancreatic necrosectomy
Drains are left for irrigation and a gastrostomy enteral feeding tube is placed
Vital signs: T 39.3oC,
BP 100/60 mm/Hg (on Levophed 2),
HR 90 bpm
Vent settings: FiO2 40%, AC 12,
TV 500, PEEP 5 mmHg, 7.38/40/132/26
ABG results
Laboratory results
WBC 28,000 cells/µl,
electrolytes OK, BUN 56,
creatinine 3.69 mg/dL,
LFTs normal
WBC, white blood cell; FiO2, fraction of inspired oxygen; AC, assist control; TV, tidal volume;
PEEP, positive end expiratory pressure; ABG, arterial blood gas; BUN, blood urea nitrogen;
LFTs, liver function tests
Microbiology
Culture results
Sputum: MSSA and MDR K. pneumoniae
(resistant to all penicillin / cephalosporins and
fluoroquinolones)
Blood: MDR K. pneumoniae (ESBL-producing)
Abdomen cultures: MDR K. pneumoniae (ESBL-producing),
Bacteroides spp.
Patient responded appropriately to tigecycline therapy for
14 days and was discharged to a sub-acute rehabilitation
facility
Clinical discussion points
regarding antibiotic choice
A. Patient-specific factors
a.
b.
c.
Allergies to various antibiotics
Prior antibiotic exposure
Clinical response to current antibiotic
B. Pharmacokinetics / pharmacodynamics and dosage of chosen drug
C. Location of the patient (hospital-acquired, hospital-associated,
community-acquired)
D. Formulary available
E. Current resistant rate within your unit, hospital, and country
F. Completeness of the surgical debridement
cSSTI case study: patient history
44-year-old man with a history of Alport
syndrome, ESRD (CRT in 1985), deafness, and
recurrent squamous cell. Remains on
tacrolimus therapy
Chief complaint: right thigh abscess after
recent
right superficial groin dissection; treated with
cephalexin (oral) without response x 5 days
Medical history: as above plus >80 squamouscell carcinomas and >40 episodes of cellulitis
after excision treated with various antibiotics
ESRD, end-stage renal disease
CRT, cadaveric renal transplant
cSSTI case study:
investigations and examinations
Allergies: no drug allergies
Vitals: T 101.3oC, HR 98 bpm, BP 120/70 mm/Hg,
respiratory rate 14
Physical exam: tense right thigh abscess over prior
suture line (skin closed) 7 x 8 cm, skin warm, markedly
erythematous
Laboratory results: WBC 12.7K cells/µl, 75% PMN,
20 bands. Electrolytes and LFTs normal. BUN 48,
creatinine 3.9 down from 5.7; 2 weeks in chronic
rejection
PMN, polymorphonuclear leukocyte
cSSTI case study
Cultures grew ESBL-producing
E. coli and MRSA
Started on tigecycline
monotherapy and treated
for 10 days
Received 4 days of tigecycline in
hospital and the rest as an
outpatient. Wound recovered
without further surgical Rx
Clinical concerns regarding
empiric antibiotic choice
A. Patient-specific factors
a.
b.
c.
d.
Infected wound and infrainguinal location
Prior antibiotic exposure
Failed 1st-generation cephalosporin therapy
Impending renal failure
C. Pathogen and hospital concerns
a.
ESRD patient population
b.
Patient location: hospital, home, facility
c.
Infection progressed on 1st-generation
cephalosporin
d.
High likelihood of harboring
at least one MDR pathogen
e.
Monotherapy vs combination therapy
f.
Knowledge of local antibiogram
g.
Formulary available
B. Source control concerns
a.
Early or delayed wound drainage /
debridement
Microbiology
3 days later the surgical site secretion culture isolated:
•
•
•
P. aeruginosa
E. faecalis
E. coli
What we did
Tigecycline therapy was given for 2 weeks
Ciprofloxacin was prescribed for 3 days
Significant clinical improvements were seen in the
lesion appearance, inflammatory parameters,
and the number of secretions
Plastic surgery was undertaken on wound site
Conclusions
•
•
•
•
cSSTIs and cIAIs usually require surgery and treatment with
broad-spectrum antibiotics and are commonly caused by MDR pathogens
Therapeutic choices for MDR pathogen management are increasingly limited
and combinations of antibiotics and/or agents held in reserve
are often used
Underlying diseases in patients with cSSTIs and cIAIs can also complicate
patient management and/or response to therapy
Tigecycline is indicated for the treatment of cSSTI and cIAI. It has a
broad-spectrum of activity against numerous MDR pathogens excluding
Pseudomonas spp. In addition:
– It does not require dose adjustments for renal or mild / moderate hepatic dysfunction
and is effective in patients with underlying comorbidities
– It can be used before carbapenems, allowing these drugs to be saved for
Pseudomonas infections