managing resistant bacterial infections€¦ · managing resistant bacterial infections professor...

Managing resistant bacterial infections

Professor Mark Wilcox

Head of Medical MicrobiologyClinical Director of Pathology

Leeds Teaching Hospitals amp University of Leeds UK

Lead on Clostridium difficile infectionHealth Protection Agency

Thanks Robin

amp Kevin

Carbapenem

Piperacillin tazobactam

3GC

Quinolone

Tigecycline

Spectrum of activity of broad-spectrum agents

Excludes ertapenem which has no Pseudomonas coverageAlthough tigecycline has demonstrated in vitro activity against atypicals these organisms are not implicated in cIAI and cSSTI the two current licensed indications for tigecycline

ANO2 PseudoAtypicalResistant Gram-

negative

Gram-negative

Gram-positive

Resistant Gram-

positive

The whole picturehellip

Selection risks associated with major antimicrobial classes

Cao B et al J Hosp Infect 200457112-18 Gerding DN Clin Infect Dis 199725(Suppl 2)S206-10Padiglione AA et al Antimicrob Agents Chemother 2003472492-8

Carsenti-Etesse H et al Clin Microbiol Infect 20017144-51Paterson DL Clin Infect Dis 200438(Suppl 4)S341-5 Carmeli Y et al Emerg Infect Dis 20028802-7

C difficile

Fluoroquinolones

3GC


Carbapenems

MDR pseudo

ESBLVREMRSA

Tigecycline and MDR Enterobacteriaceae

bull Systematic review microbiological activity and clinical effectiveness of tigecycline for multidrug-resistant (MDR) Enterobacteriaceae

bull 26 microbiological amp 10 clinical studies were identified

bull FDA (MIC lt2 mgL) or EUCAST (lt1 mgL) breakpoints

Kelesidis T et al J Antimicrob Chemother 200862895-904



bull In clinical studies 697 of the 33 reported patients treated with tigecycline achieved resolution of an infection caused by a carbapenem-resistant or ESBL-producing or MDR Enterobacteriaceae


Fosfomycin and MDR Enterobacteriaceae


bull 17 microbiological studies n=5057 isolates including 4448 ESBL +ve

bull 11 of the 17 studies reported that at least 90 of the isolates were susceptible to fosfomycin

bull Using a provisional MIC breakpoint lt64 mgLE coli (n=1657) 968 susceptibleKlebsiella spp (n=748) 813 susceptible

Falagas M et al Lancet Infect Dis 20101043-50


bull In two clinical studies oral treatment with fosfomycin-trometamol was clinically effective against complicated or uncomplicated lower UTIs caused by ESBL-producing E coli in 75 (938) of 80 patients


Piperacillin-tazobactam and MDR Enterobacteriaceae

bull Italian hospital with increased prevalence of Proteus mirabilis strains producing acquired AmpC-type beta-lactamases (CBLs)

bull 43 CBL-positive isolates were obtained from hospitalised (n=22) and non-hospitalised (n=21) patients (median age 788 years) ndash usually UTIs

bull Treatment with amikacin or carbapenems was consistently effective

bull Piperacillintazobactam produced a clinical response in seven of nine cases

Luzarro F et al int J Antimicrob Agents 200933328-33








bull b-lactamndashb-lactamase inhibitor agents on patients infected with ESBL-producing strains of E coli and Klebsiella spp

bull 7 medical centres across North Americabull 148 patient records reviewedbull 30 rcvd FQ 18 carbapenem 16 pip-tazo 9 other b-

lactams 7 ampndashsul 6 aminogly 6 co-trimoxbull 83 given monotherapybull 23 rcvd pip-tazo (17 infections outside the urinary tract)bull For infections with pathogen MIC of pip-tazo lt16 mgfrasl L

successful outcome was reported in 1415 (1011 non-UTIs)bull Only 15 non-UTIs responded when pip-tazo MIC gt16 mgfrasl Lbull Meropenem therapy was successful in 24 pip-tazo resistant

infectionsGavin PJ et al int J Antimicrob Agents Chemother 2006502244-7


bull 43 episodes of E coli bacteraemia caused by ESBL-producing strains (primarily CTX-M-14)

bullbull Mortality was lower when patients were given a b-lactamndashb-

lactamase inhibitor combination or carbapenem as compared with either a cephalosporin or FQ

(9vs 35 p 005)bullbull E coli 100 susceptible to meropenem 95 to piperacillinndash

tazobactam 26 to ciprofloxacin and 0 to cephalosporins

Rodrıguez-Bano J et al Clin Infect Dis 2006431407-14

Tigecycline for MDR A baumanniiMetan G et al Clinical experience with tigecycline in the treatment of carbapenem-resistant Acinetobacter infections J Chemother 2010 Apr22(2)110-4

Gordon NC Wareham DW A review of clinical and microbiological outcomes following treatment of infections involving multidrug-resistant Acinetobacterbaumannii with tigecycline J AntimicrobChemother 2009 Apr63(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 Mar18(1)27-34

Tigecycline for MDR A baumanniibull Retrospective study of patients who received tigecycline for

tige-S carbapenem-R Acb-complex infections 2008-09bull 21 patients (median age 48 years) median duration tige 14 dbull 18 patients were treated with tigecycline as the sole pathogenbull Most common indication for tigecycline was SSI (VAP)bull Tigecycline was the sole antibiotic in 7 patientsbull 2 patients died within 14 days 4 died within 30 daysbull 1721 lsquohad successful clinical outcomesrsquo BUT 1421 had

microbiological failurebull Poor correlation between micro and clinical responsebull Clinical failure was more common in patients with VAPbull Patients with bacteraemia or VAP more likely to have

microbiological failureMetan G et al J Chemother 201022110-4

Colistin for MDR A baumanniibull 166 consecutive patients infected or colonised with

carbapenem- and MDR A Baumannii

bull 18 hospitals (London UK) 141 belonged to OXA-23 clone 1

bull Only colistin and tigecycline retained good in vitro activity with 994 and 819 of isolates susceptible respectively

bull 62 patients in ICU or HDU 84 (506) infected

bull Survival rates among infected and colonised patients were 68 and 67 indicating little attributable mortality

Livermore D et al Int J Antimicrob Agents 20103519-24

Colistin for MDR A baumanniibull Univariate and multivariate analyses

ndash poorer outcomes among ICU-infected patients pulmonary infection or bacteraemia

ndash trauma patients had significantly better outcomebull Outcomes varied by hospital (multivariate analysis) CASE MIXbull Poor association between outcome and therapy with colistin

(andor tigecycline)bull Patients with respiratory infection 1215 treated with

intravenous colistin alone had poor outcome compared with 18 whose therapy include nebulised colistin (P=0003)

BUT the patients receiving nebulised drug were mostly younger included trauma cases and were at a hospital with good outcomes


Tigecycline in ICU setting

Swoboda et al J Antimicrob Chemother 2008

APACHE Acute Physiology and Chronic Health EvaluationSOFA Sequential Organ Failure Assessment

Enterococcus durans

Enterobacter cloacae

Enterococcus casseliflavus or Enterococcus gallinarum

Burkholderia cepacia

Acinetobacter baumannii

Enterococci species not determined

MRSA

Enterococcus faecalis

Infection of unknown origin

Strenotrophomonas maltophilia

VRE

Enterococcus faecium

Microorganism

1 (1)

1 (1)

1 (1) 1 (1)

1 (1)

4 (6) 4 (6)

7 (10)

11 (16)

13 (19)

15 (21)

26 (37)

Infections n ()

bull APACHE II scores 27 plusmn 10 SOFA 12 plusmn 3bull Overall mortality 30

n=70 withindication

0

10

20

30

40

50

60cIAI

cSSTI

Mixed

Other

bull Mean duration of tigecycline therapy was 9 +- 4 daysbull 76 of patients received tigecycline in combination

(64 second line)bull APACHE score and renal replacement were identified

as predictive factors for mortalitybull AUTHOR CONCLUSIONS lsquoTigecycline 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 agentsrsquo



Antibiotics and risk of CDI

Evidence to supportthe restriction

of these as a controlmeasure for CDI

CDI may still occur

Need to minimise all antibiotic use polypharmacy and duration

Medium risk Low riskHigh risk

CephalosporinsClindamycin

AmpicillinamoxycillinCo-trimoxazole

MacrolidesFluoroquinolones

AminoglycosidesMetronidazole

Anti-pseudomonal penicillins +

β-lactamase inhibitorsTetracyclinesRifampicin

Vancomycin

Baines SD et al J Antimicrob Chemother 200555974-82Baines SD et al J Antimicrob Chemother 2006581062-5

Induction of C difficile toxin production

Tigecycline and C difficilebull Tigecycline is highly active (MIC=006 mgL) against C difficile

Baines SD et al J Antimicrob Chemother 2006581062-5

bull No in vitro evidence of increased risk of tigecycline-induced CDIBaines SD et al J Antimicrob Chemother 2006581062-5

bull No in vivo evidence of increased risk of tigecycline-induced CDIWilcox MH Clin Microbiol Infect 200713949-52

bull Some evidence that tigecycline could be used to treat CDI (THIS IS NOT A LICENSED INDICATION)Herpers BL et al Clin Infect Dis 2009481732-5

Lu CL et al Int J Antimicrob Agents 201035311-2

The missing care bundle antibiotic prescribing in hospitalsCooke FJ Holmes AHInt J Antimicrob Agents 20073025-9Department of Infectious Diseases and Immunology Hammersmith Hospitals NHS Trust Imperial CollegeDu Cane Road London W12 0HS UK

The care bundle involves grouping together key elements of care for procedures and the management of specific diagnoses in order to provide a systematic method to improve and monitor the delivery of clinical care processes In short care bundles aim to ensure that all patients consistently receive the best care or treatment all of the time This approach has been successfully applied to the management of various conditions particularly in the critical care setting The Institute for Healthcare Improvements 100K lives campaign consisted of six care bundles three of which have addressed preventing hospital-acquired infection The UK Department of Healths delivery programme to reduce healthcare-associated infections (HCAIs) including methicillin-resistant Staphylococcus aureus (MRSA) includes six high-impact interventions which are care bundles to reduce HCAIs However we suggest that one key intervention is missing and consider this intervention will be increasingly important if hospitals are to address the rising incidence of Clostridium difficile to tackle antibiotic resistance and to improve patient care The missing intervention addresses the process of antibiotic prescribing We propose that the time is right to consider the application of the care bundle approach to improve the prescribing of antibiotics both for treatment and prophylaxis

The antibiotic prescribing bundle

bull Use monotherapy whenever possible for initial (empiric) treatment

bull Optimise dose and duration

bull Perform a regular risk assessment

ndash For each patient

ndash Impact of the programme

Aminoglycosides

Glycopeptides

LipopeptidesOxazolidinones

Monotherapy or

combinationCarbapenems

BLICsCephalosporins

Fluoroquinolones

Tigecycline

Empiric choice Empiric choice 2nd 3rd line Final option

Low resistance risk and minimal

complexity

Increased resistance risk

and complexity

Treatment failure

[Cef Met prophylaxis]

Not if intravascular infectionNot in VAP as monotherapy

Antibiotic choice in high-risk patients

bull Capacity to cover resistant pathogens

bull Proven efficacy in MDR infection

bull Pharmacokinetic and pharmacodynamic profile

bull Safety profile

bull Capacity not to induce lsquoovergrowthrsquo eg CDI

bull Low potential for inducible resistance

bull Capacity not to select for resistant pathogens

Should consider measures to reduce use of 3GCs FQs amp carbapenems

Increased reliance on carbapenemsmay accelerate emergence of completely resistant isolates


Slide Number 2


Slide Number 4



Slide Number 7








Tigecycline for MDR A baumannii


Colistin for MDR A baumannii






Tigecycline and C difficile

Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32

Thanks Robin

amp Kevin

Carbapenem


3GC

Quinolone

Tigecycline




negative

Gram-negative

Gram-positive

Resistant Gram-

positive





C difficile

Fluoroquinolones

3GC


Carbapenems

MDR pseudo

ESBLVREMRSA




































































Enterococcus durans






MRSA




VRE


Microorganism

1 (1)

1 (1)

1 (1) 1 (1)

1 (1)

4 (6) 4 (6)

7 (10)

11 (16)

13 (19)

15 (21)

26 (37)

Infections n ()


n=70 withindication

0

10

20

30

40

50

60cIAI

cSSTI

Mixed

Other










CDI may still occur









Vancomycin

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32

Carbapenem


3GC

Quinolone

Tigecycline




negative

Gram-negative

Gram-positive

Resistant Gram-

positive





C difficile

Fluoroquinolones

3GC


Carbapenems

MDR pseudo

ESBLVREMRSA




































































Enterococcus durans






MRSA




VRE


Microorganism

1 (1)

1 (1)

1 (1) 1 (1)

1 (1)

4 (6) 4 (6)

7 (10)

11 (16)

13 (19)

15 (21)

26 (37)

Infections n ()


n=70 withindication

0

10

20

30

40

50

60cIAI

cSSTI

Mixed

Other










CDI may still occur









Vancomycin

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32





C difficile

Fluoroquinolones

3GC


Carbapenems

MDR pseudo

ESBLVREMRSA




































































Enterococcus durans






MRSA




VRE


Microorganism

1 (1)

1 (1)

1 (1) 1 (1)

1 (1)

4 (6) 4 (6)

7 (10)

11 (16)

13 (19)

15 (21)

26 (37)

Infections n ()


n=70 withindication

0

10

20

30

40

50

60cIAI

cSSTI

Mixed

Other










CDI may still occur









Vancomycin

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32




































































Enterococcus durans






MRSA




VRE


Microorganism

1 (1)

1 (1)

1 (1) 1 (1)

1 (1)

4 (6) 4 (6)

7 (10)

11 (16)

13 (19)

15 (21)

26 (37)

Infections n ()


n=70 withindication

0

10

20

30

40

50

60cIAI

cSSTI

Mixed

Other










CDI may still occur









Vancomycin

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32










CDI may still occur









Vancomycin

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32

















Aminoglycosides

Glycopeptides


Monotherapy or


BLICsCephalosporins

Fluoroquinolones

Tigecycline



complexity


and complexity

Treatment failure







bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32





bull Safety profile







Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32


Slide Number 2


Slide Number 4



Slide Number 7

















Slide Number 24

Slide Number 25


Slide Number 27


Slide Number 29

Slide Number 30

Slide Number 31

Slide Number 32

managing resistant bacterial infections€¦ · managing resistant bacterial infections professor...

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