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When I use….Ertapenem

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When I use….Ertapenem Powered By Docstoc
					When I would use….Ertapenem

            Graeme Jones
 Consultant in Medical Microbiology
     HPA SE Regional Laboratory
Southampton University Hospitals Trust
                Ertapenem
• New 1-ß-methyl carbapenem licensed in 2003

• Significantly different properties from
  existing carbapenems

• Significantly different uses
            Carbapenem properties
               Ertapenem   Imipenem - Meropenem
                           Cilastatin
Stable to  Yes             No         Yes
renal DHP1
Metabolism Renal           I: Hepatic   Renal
                           C: Renal
Protein        ~94%        20%          <10%
bound
Half life      4h          1h           1h
  Ertapenem Human Pharmacokinetics
                                    Healthy Volunteers Single 1g dose
      [Total Ertapenem]PL (mg/L)

                           1000
                                                                        IV
                                                                        IM
                                   100
                                                                Half-life ~
                                                                   4h
                                    10
                                                                      2 mg/L

                                    1
                                         0 2 4 6 8 10 12 14 16 18 20 22 24
                                                     Time, hr
Bioavailability of IM Ertapenem > 90%
Relative activity of Carbapenems
 Gram-Positive               Gram-Negative
 Activity                    Activity




             Imipenem
                        Ertapenem
                           Meropenem
Organism         Ertapenem        Imipenem        Meropenem
                 MIC50    MIC90   MIC50   MIC90   MIC50   MIC90
E. faecalis       8       ≥16     2       4       8       8
E. faecium        >16     ≥16     ≥16     ≥16     32      64
MSSA              0.25    0.5     0.03    0.12    0.06    0.5
MRSA              >16     ≥16     16      ≥16     8       32
S. pneumoniae     0.03    0.03    0.016   0.03    0.008   0.5
Acinetobacter spp 16      ≥16     0.5     2.0     0.25    2.0
Citrobacter spp   0.016   0.25    0.5     2.0     0.02    0.06
Enterobacter spp 0.03     0.5     1.0     2.0     0.03    0.13
E. coli           0.016   0.06    0.25    0.5     0.06    0.06
P. aeruginosa     4-8     ≥16     2       4       0.25    4
            Carbapenem Uses
Ertapenem          •1st line for complicated
                   community-acquired infection
                   •Low risk of Pseudomonas/
                   Acinetobacter infection
                   •Directed therapy
Imipenem           •2nd/3rd line for serious
                   hospital-acquired infection
Meropenem
                   •High risk of Pseudomonas/
                   Acinetobacter infection
                   •Directed therapy
        RCTs involving Ertapenem

Context            Comparator               Equivalence
Intra-abdominal    Pip/Taz 3.375g 6h        Yes
infection
                   Ceftriaxone 2g od +      Yes
                   Metronidazole 500mg 8h
Pelvic infection   Pip/Taz 3.375g 6h        Yes

Complicated SSTI   Pip/Taz 3.375g 6h        Yes

Community -        Ceftriaxone 2g od        Yes
acquired pneumonia
Complicated UTI    Ceftriaxone 2g od        Yes
             Toxicity Issues
• Licensed in USA but not EU for use in
  significant renal impairment (CrCl <30ml/min)

• Increased LFTs
• Neutropaenia
• Low incidence of seizures
            Resistance issues
• Does ertapenem select for acquired carbapenem
  cross-resistance in E coli?

• Does ertapenem select for colonisation with
  intrinsically resistant microbes?

• Does ertapenem select for acquired carbapenem
  cross-resistance in Pseudomonas/ Acinetobacter
     Acquired carbapenem cross-resistance in
           Pseudomonas aeruginosa?

     • At 2-8x MIC ertapenem selected for porin-deficient
       and efflux up-regulated mutants of P. aeruginosa

     • Addition of 20% serum resulted in four-fold increase
       in ertapenem concentration needed to select mutants.

     • At sub-MIC concentrations overgrowth of parent
       strain occured, not selection of resistant mutants
Livermore DM et al JAC Feb 2004 on-line access
Acquired carbapenem cross-resistance in
      Pseudomonas aeruginosa?
• Free ertapenem concentration falls below
  4mg/l (lower limit MIC50) within 4h in vivo

• Risk of ertapenem selecting carbapenem
  cross-resistant P.aeruginosa mutants is low
            Which Carbapenem?
                       Advantages       Disadvantages

Meropenem              Empirical cover Cost
(1g tds=£86/day)

Imipenem               Empirical cover Caution in renal
(500mg qds =£48/day)                    impairment
Ertapenem              Cost             Limited
(1g od = £32/day)      Once-daily       spectrum
                       Less resistance?
        Using Ertapenem in
Southampton University Hospitals Trust
• Non-formulary
   – use restricted to recommendation of Microbiology Service
   – Control via combined Microbiology/Pharmacy
     wardrounds
• Majority of use for directed therapy
   – confirmed ESBL-producing coliform infection
   – OPAT
   – Rare empirical use for presumed ESBL-producing
     coliform infection
                            ESBL ISOLATES




              0
                  10
                       20
                            30
                                 40
                                      50
                                           60
                                                70
                                                     80
                                                          90
       Jan
       Feb
       Mar
       Apr
       May
       Jun
        Jul




2002
       Aug
       Sep
       Oct
       Nov
       Dec
       Jan
       Feb
       Mar
       Apr
       May
       Jun
        Jul




2003
       Aug
       Sep
       Oct
       Nov
       Dec
       Jan
       Feb
       Mar
       Apr
       May
       Jun
        Jul
2004



       Aug
       Sep
       Oct
                                                                  January 2002- December 2004




       Nov
       Dec
                                                               Isolation of ESBL-producing E. coli
              E. coli bacteraemias from SUHT
                  1 January 2002 - Present
                                 non-ESBL        ESBL
         80
         60
number




         40
         20
         0
               1     2   3   4    1   2      3       4   1   2   3   4
                                          quartile
              2002                 2003                  2004
                   Carbapenem use in SUHT 2003-2004

                0.08

                0.07

                0.06
WHO DDD / FCE




                0.05
                0.04                                                     Imipenem
                                                                         Meropenem
                0.03                                                     Ertapenem
                0.02

                0.01

                  0
                       Jan-Jun   Jul-Dec 2003   Jan-Jun   Jul-Dec 2004
                         2003                     2004
                                  Ertapenem use in SUHT by
                                     directorate 2003-2004
                                    Jul - Dec 2003                   Jan - Jun 2004

                   30
WHO DDD/1000 FCE




                   25
                   20

                   15
                   10
                    5
                    0
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                                                                                O
                                                                 N
            Ertapenem and
Outpatient Parenteral Antibiotic Therapy
Directed therapy
  –   ESBL-producing E. coli infection
  –   Complicated soft-tissue infection
  –   Complicated bone/joint infection
  –   Complicated intra-abdominal abscess
                  Ertapenem
• Once-daily carbapenem

• Active against a broad spectrum of community-
  acquired pathogens including AmpC and ESBL-
  producing coliforms

• No useful activity against Pseudomonas aeruginosa
  / Acinetobacter spp

• May be less selective for carbapenem resistance in
  Pseudomonas aeruginosa.

				
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posted:4/6/2010
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