1 CARBAPENEMS; DRUG RESISTANCE; ANTI BACTERIAL … · Ertapenem, imipenem, meropenem, and doripenem...
Transcript of 1 CARBAPENEMS; DRUG RESISTANCE; ANTI BACTERIAL … · Ertapenem, imipenem, meropenem, and doripenem...
1 – CARBAPENEMS;
2 – DRUG RESISTANCE;
3 – ANTI BACTERIAL ACTIVITY;
4 – PHARMACOLOGY;
5 – ADVERSE REACTIONS;
6 – CLINICAL USE;
7 – RECOMMENDED DOSES.
CARBAPENEMS
♠Four carbapenems -- imipenem, meropenem, ertapenem,
and doripenem -- are approved for clinical use;
♠In Japan, panipenem, biapenem, and tebipenem, are
approved.
♠Carbapenems are active against a broad range of gram-
positive and gram-negative aerobic and anaerobic bacteria;
♠Carbapenems inhibit cell wall synthesis.
Is mediated by one or a combination of the
following mechanisms:
(1) Production of β-lactamase that hydrolyzes carbapenems;
(2) Diminished permeability due to impaired expression of
certain outer membrane proteins;
(3) Efflux of drug across the outer membrane;
(4) Production of an altered or low-affinity target, which is
more relevant in gram-positive bacteria.
Increasing incidence of carbapenem-resistant
Enterobacteriaceae (CRE), including NDM-1 (New
Delhi metallo-β-lactmase-1) and KPC (Klebsiella
pneumoniae carbapenemase), has aroused concern
about utility of this important class of antibacterial
agents.
Carbapenemase-producing Klebsiella pneumoniae
strains (CPK) are highly resistant to all carbapenems.
The carbapenems have similar antibacterial spectra.
All have excellent in vitro activity against gram-positive
cocci in general.
Oxacillin-resistant strains are highly resistant to currently
available carbapenems.
Enterococcus faecalis is typically susceptible to imipenem
with MICs of 2 μg/mL or less, but is more resistant to
ertapenem, meropenem, and doripenem.
None of the carbapenems is active against E.
faecium.
Neisseria gonorrhoeae and Neisseria meningitidis
are highly susceptible to carbapenems with MICs
typically less than 0.1 μg/mL.
Ceftriaxone-resistant N. gonorrhoeae remains fully
susceptible to ertapenem.
Doripenem is the most active carbapenem against
P. aeruginosa;
Ertapenem has no activity against P. aeruginosa.
Carbapenems are highly active against most obligatory
anaerobic species, including anaerobic gram-positive
cocci, Bacteroides fragilis, non-fragilis species of
Bacteroides, Clostridium spp. with the exception of
Clostridium difficile.
Nocardia spp. are inhibited by carbapenems.
Ertapenem, imipenem, meropenem, and doripenem are
formulated as parenteral agents because they are absorbed
poorly after oral ingestion.
The plasma half-life is 1 hour for imipenem, meropenem, and
Doripenem, and 4 hours for ertapenem.
The longer half-life of ertapenem is due to extensive protein
binding (>90%) compared with imipenem (20%), meropenem
(2%), and doripenem (8%) and permits once-daily dosing.
Ertapenem is typically administered once daily;
Imipenem every 6 hours, meropenem and doripenem every 8
hours.
All carbapenems undergo extensive renal elimination and thus
require dosage adjustment in patients with reduced renal function,
but not in patients with impaired liver function.
Between 30% and 50% of ertapenem, imipenem, meropenem, and
doripenem is removed by hemodialysis.
Carbapenems are well distributed to various body compartments
and penetrate well into most tissues.
Carbapenems are generally well tolerated.
There seems to be no particular propensity for
them to cause major adverse effects;
The most common adverse events are: nausea,
vomiting, diarrhea, rash, headache, and
phlebitis, occurring in 1% to 3% of patients.
All carbapenems have been associated with
seizures, believed to be related to their structural
similarity with γ-aminobutyric acid (GABA) and
antagonism at the receptor site.
The overall incidence is low, but the risk is elevated
in patients with renal failure and neurologic
comorbidities.
Seizures are more common with imipenem (1% to 2%).
The incidence of imipenem and meropenem
hypersensitivity has been estimated to be less than 3% in
the general population.
Drug interactions are uncommon, though the
combination of valproic acid and carbapenems leads to
grossly subtherapeutic valproic acid levels.
Carbapenems have been considered potentially cross-
allergenic with penicillins.
patients with a positive skin test to penicillins for
IgE-mediated (immediate) hypersensitivity, rarely
have a positive skin test to carbapenems (<1%);
Therefore, administration of a carbapenem is
considered safe in patients with history of penicillin
immediate hypersensitivity if their skin test is
negative for that carbapenem.
Carbapenems display broad-spectrum
activity covering:
Gram-positive,
Gram-negative,
And anaerobic bacteria;
Carbapenems are useful for treatment of a wide variety of
moderate to severe infections, including:
Bacteremia,
Hospital-acquired pneumonia,
Intra-abdominal infections,
Complicated urinary tract infections,
Bone and soft tissue infections,
And obstetric and gynecologic infections.
Meropenem is the only carbapenem
approved by the FDA for treatment of
bacterial meningitis.
Imipenem should be avoided because
of its propensity to cause seizures.
Carbapenems are generally active against
cephalosporin-resistant Enterobacteriaceae
producing ESBLs and AmpC β-lactamases,
but not those producing KPC β-lactamases.
Ertapenem has only limited activity against
enterococci and lactose nonfermenting gram-
negative species including P. aeruginosa.
Unfortunately, the worldwide spread
of carbapenem-resistant strains has
threatened the effectiveness of all
β-lactams for treatment of
Acinetobacter infections.
Imipenem, meropenem, and doripenem are therapeutically
equivalent and interchangeable in most clinical situations;
Imipenem is slightly more active against gram-positive
organisms than meropenem and doripenem (especially E.
faecalis);
Meropenem and doripenem are slightly more active against
gram-negative organisms than imipenem.
In P. aeruginosa, resistance to imipenem is not always predictive
of resistance to meropenem or doripenem, and vice versa.
Imipenem, meropenem, and doripenem
are all appropriate for use in the
treatment of hospital-acquired infections
because of their antipseudomonal
activity.
Doripenem is the most active
carbapenem against P. aeruginosa
in vitro.
Imipenem: 250 to 500 mg every 6 hours, or 1 g every 8 hours
intravenously;
Meropenem: 500 mg to 1 g every 8 hours;
-- For treatment of severe infections, up to 6 g/day;
Doripenem: 500 mg every 8 hours;
Ertapenem: 1 g daily;
Ertapenem differs from other carbapenems in two important respects:
1 -- It has a long half-life, permitting once-daily dosing;
2 -- It has relatively poor activity against P. aeruginosa and A. baumannii.
Aztreonam is the only monobactam currently approved by the FDA.
Aztreonam is well tolerated.
Aztreonam is not absorbed from the gastrointestinal tract.
It has a broad spectrum of activity against gram-negative bacteria, but has
no activity against gram positive or anaerobic bacteria.
Some P. aeruginosa, Enterobacter cloacae, and Citrobacter freundii strains
are resistant.
Aztreonam is renally excreted, with 60% to 65% recovered in urine.
Dose adjustment is not necessary in patients with chronic hepatic disease if
renal function is not impaired.
Aztreonam is cleared by continuous venovenous hemofiltration,
hemodialysis, and peritoneal dialysis.
Standard hemodialysis removes about half of a 1-g dose given just
before dialysis.
Cross-reactivity with penicillins and cephalosporins is extremely rare,
even in patients with immunologically proven hypersensitivity to other β-
lactams, though caution is still recommended in the setting of repeated
exposure to aztreonam.
Aztreonam is rarely used alone empirically, because its spectrum of
activity is limited entirely to aerobic gram-negative bacteria.
The usual dose:
“1 to 2 g every 6 to 8 hours IV or IM”
Daily dose for serious infections:
Up to 6 g.
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