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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