Carbapenems

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 Outline
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 Spectrum of activity
Drug Strep Enterobacteria Non- Anaerobes
spp.&MSSA ceae fermentors

Imipenem + + + +
Meropenem + + + +

Ertapenem + + +
Doripenem + + + +
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 Carbapenems
Imipenem:

• Broad spectrum, covers Gram positive, Gram negative (including ESBL),

Pseudomonas and anaerobes.
• slightly more active against Gram-positive bacteria than are other
carbapenems.
• It is not approved by the US Food and Drug Administration (FDA) for
meningitis, and should be avoided in the treatment of central nervous
system infections because of its propensity to cause seizures in patients
with elevated risk factors, e.g. renal failure or structural brain disease.

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• Imipenem is excreted renally, with 70% of imipenem recovered in the urine
within 10 h and no detectable urinary excretion after that time.
• Accumulation is not observed in plasma or urine, even with regimens
administered as frequently as every 6 h.
• Imipenem is distributed extensively in tissues and fluids.
• The recommended adult dose of imipenem for patients with normal renal
function is 250 mg to 1 g intravenously every mg. 6–8 h. The pediatric
dose is 15–25 kg every 6–8 h.
• Dose adjustment is required for patients with creatinine clearance of less
than 50 min or body weight of less than 70 kg.
• The low stability of imipenem (10% degradation at 25 C after 3.5 h) limits
the possible duration of infusion of this carbapenem; it must therefore be
dosed as 30–60-min infusions.

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Meropenem:

• Less seizure-inducing potential, can be use to treat CNS infection.

• Meropenem is approved by the US FDA for the treatment of bacterial
meningitis in children aged 3 months and older, and is efficacious in
adults.
• The recommended adult dose of meropenem for patients with normal
renal function is 500–1000 mg intravenously every 8 h, although daily
doses of 6 g seem to be safe. The pediatric dose is 20–40 kg every 6–8 h.
• Dose adjustment is required for patients with creatinine Clearance of less
than 50 min. Some investigators have dosed meropenem as a 3-h infusion
in an attempt to improve efficacy against resistant pathogens.

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Ertapenem:

• Lack activity against Acinetobacter and Pseudomonas

• Has limited activity against penicillin resistant pneumococci
• Elimination follows non-linear kinetics, partly owing to the concentration
dependence of protein binding. Approximately 80% of excretion is via the
kidneys, with half as the native compound and half as the open-ring
derivative; a further 10% is eliminated via the feces.
• Ertapenem possesses a longer apparent elimination half-life than imipenem
and meropenem. This longer half-life allows for a convenient, once-daily
administration schedule.

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• Ertapenem is an important option for the empirical treatment of complicated
community-acquired bacterial infections, where a mixed flora of anaerobes
and aerobes is likely, e.g. community-acquired pneumonia, complicated skin
and skin structure infection, complicated urinary tract infection, or
community-acquired complicated intra-abdominal infection, in both children
and adults.
• It lacks antimicrobial activity against non-fermenting Gram negatives
such as P. aeruginosa and Acinetobacter spp., and thus cannot be used
when they are suspected pathogens.

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Doripenem:

• Doripenem is licensed for adults for the treatment of complicated intra-

abdominal infections and complicated urinary tract infections, including
pyelonephritis, in the USA.
• It is undergoing regulatory review for the treatment of complicated urinary
tract infections and intra-abdominal infections in Europe, and for the
treatment of nosocomial pneumonia, including ventilator-associated
pneumonia, in both the USA and Europe.
• A clinical trial comparing doripenem and imipenem for the treatment of
ventilator-associated pneumonia showed less emergence of resistance
among P. aeruginosa isolates in the doripenem arm, although the
numbers were modest and the clinical outcomes were the same in both
groups.
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• Its renal elimination is similar to that of meropenem, with a mean
urinary recovery, of doripenem, of 75% over 24 h.
• The MICs of doripenem are lower for P. aeruginosa than are those
of other antipseudomonal agents.
• When compared with several other antipseudomonal agents,
including other carbapenems, doripenem was associated with the
lowest rate of spontaneous resistance in vitro.
• When it was combined with an aminoglycoside in vitro, doripenem
resistance selection in P. aeruginosa was decreased even further.
• Against a wide range of bacteria, doripenem can be safely
combined with various antimicrobial agents (amikacin, co-
trimoxazole, levofloxacin, daptomycin and linezolid) without risk of
antagonism.
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Carbapenem Resistant
Enterobacteriaceae (CRE)
 Enterobacteriaceae

Gram-negative microorganisms

Common pathogens: Escherichia coli, Klebsiella spp.,

Proteus spp., Enterobacter spp. and Serratia spp.

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Carbapenem-Resistant
Enterobacteriaceae (CRE)

 Different mechanisms of resistance

 Production of carbapenemases: carbapenem-hydrolyzing
beta-lactamases
 KPC (K. pneumoniae carbapenemase)
 MBL (metallo-beta lactamases) e.g. NDM-1 (New Delhi
metallo-beta-lactamase)
 OXA-carbapenemase
 Resistant to ALL penicillins, cephalosporins, and
carbapenem
 Activity may be encoded on chromosomes or plasmids.
 Concurrent resistance genes (e.g. fluoroquinolones and AG)
are common.
 CRE can spread from person to person
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 MECHANISMS OF RESISTANCE
AGAINST CARBAPENEMS

 Mechanisms of resistance to carbapenems include production of

β-lactamases, efflux pumps, and mutations that alter the
expression and/or function of porins and PBPs .
 Combinations of these mechanisms can cause high levels of
resistance to carbapenems in certain bacterial species, such as
Klebsiella pneumoniae, P. aeruginosa, and A. baumannii.

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Klebsiella Pneumoniae Carbapenemase
• KPC is a class A b-lactamase
• Confers resistance to all b-lactams including extendedspectrum
cephalosporins and carbapenems
• Occurs in Enterobacteriaceae
• Most commonly in Klebsiella pneumonia
• Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp.,
Escherichia coli, Salmonella spp., Serratia spp.,
• Also reported in Pseudomonas aeruginosa (Columbia)

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 Carbapenem resistance
Enterobacteriaceae (CRE)

the Clinical and Laboratory Standards Institute guideline 2016

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 Resistance to imipenem and meropenem in Enterobacteriaceae during 2000-2012

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Yanling Xu, et al. Epidemiology of CRE during 2000-2012 in Asia. Journal of Thoracic Disease 2015;7(3):376-385.
• The prevalence of CRE,
according to some institutions
in epidemic area, varies
24.7% - 29.8%.

Prevalence of CRE in different Asian countries

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Yanling Xu, et al. Epidemiology of CRE during 2000-2012 in Asia. Journal of Thoracic Disease 2015;7(3):376-385.
 • Pathogen distribution of CRE in Asia

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Yanling Xu, et al. Epidemiology of CRE during 2000-2012 in Asia. Journal of Thoracic Disease 2015;7(3):376-385.
 Causes of CRE infection
• Overspill of bacteria from their primary sites
(These germs are found in normal human intestines/gut).
• Infection from community acquired/environment

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Yanling Xu, et al. Epidemiology of CRE during 2000-2012 in Asia. Journal of Thoracic Disease 2015;7(3):376-385.
 Carbapenem resistance
Enterobacteriaceae (CRE)

Non-carbapenemase Carbapenemase
producing CRE producing CRE
1. Active transport drugs out of the cell
2. Mutation - loss of porin or outer membrane

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Class of carbapenemase

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Role of Carbapenemase

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Treatment of CRE
 Wild type Enterobacteriaceae
standard therapy including “Carbapenem” antibiotics

 CRE Colistin
“Carbapenem” antibiotics
Fosfomycin
Double carbapenem? Tigecycline
Aminoglycosides
Polymyxin B 30
Treatment Options for CRE
• Combination therapy with 2 or more agents is recommended,
especially for severe infections
• Improved mortality
• Polymyxins: colistin and polymyxin B
• Fosfomycin (for UTI)
• Tigecycline
• Aztreonam
• Carbapenems in combination with other agents
• Synergy and additive activity
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 Tigecycline
 Glycylcycline (tetracycline derivative)
 Broad-spectrum activity against many resistant GPC and GNB & anaerobes
 S. pneumoniae, S. aureus/MRSA, E. faecium
 H. influenzae, Enterobacter, E.coli, Klebsiella, Serratia, Citrobacter, Shigella, Salmonella
 Pseudomonas, Providencia, Proteus & Morganella are RESISTANT!

 Bacteroidis fragilis, Clostridium perfringens

 Major side effects
 N/V (~20% of patients)

 Post-marketing reports of pancreatitis

 Tigecycline
 Practical uses
 MDR gram negative organisms

Acinetobacter spp., ESBLs, KPCs

 Limitations
 Emergence of resistance among GNR during treatment

 Nausea/Vomiting

Reduced if patients are eating or co-administered with

ondansetron
 Avoid use as monotherapy in severely ill patients

Increased risk of death (FDA warning)

 Colistin
 An old fellow! (… used in the 1960s)
 Detergent effect disrupting the cell membrane
 Rekindled interest nowadays:
 pan-resistant P aeruginosa and Acinetobacter
 Adverse effects
 Nephrotoxicity: up to 20-30%, reverses
 Neurotoxicity: seizures, ataxia, weakness
 Fosfomycin
 Unique mechanism of action
 Inhibits enzyme involved in peptidoglycan synthesis
 Bactericidal
 Retains high and prolonged urinary concentrations
 No cross-resistance
 Retains activity against many MDR organisms
 Rapid resistance when used as monotherapy
 May have synergy with other antimicrobials
 aminoglycosides

Cai Y et al. J Antimicrob Chemother. 2009;64:563-66.

 Fosfomycin PK
 Only approved as an oral formulation in US for uncomplicated UTI
 3g x 1 dose

 Low systemic absorption

 Well-tolerated

 Decreased side effects (GI disturbances)

 Remains therapeutic for days

 Unlabeled q48-72hr dosing for complicated UTI x21 days

 Data lacking for upper UTI

 IV option available in Europe for cSSSIs

 Compared to linezolid
Possible Combinations for CRE
 Colistin PLUS tigecycline
 Colistin PLUS aminoglycoside IV (if susceptible)
 May consider tobramycin (inhaled) for pneumonia for less systemic
absorption
 Colistin PLUS rifampin IV/PO
 Rifampin has synergistic activity for MDR gram-negatives

 Colistin PLUS a carbapenem

 Strain does not have to be susceptible to carbapenem

 Ampicillin-sulbactam ± Colistin
 Sulbactam alone is effective against A. baumannii

Pachon-Ibanez ME et al. J Antimicrob Chemother. 2010;54(3):1165-1172.

Drug in Late Stage (Phase 3) Clinical
Development With Activity Against
Carbapenem-Resistant Enterobacteriaceae
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