|
Cefepime (Maxipime®, Dura) has been
designated the preferred third generation cephalosporin at the University
of Kentucky Hospital. Ceftazidime and cefotaxime have been removed from
the formulary and are available for use
only in meningitis or pseudomonal
infections (see tables, page 2). These changes were made because:
-
Cefepime is an
extended-spectrum cephalosporin that combines the Gram-negative activity
of ceftazidime with the Gram-positive activity of cefotaxime. The
Gram-negative spectrum, which includes Pseudomonas aeruginosa, is
at least equal to ceftazidime.
-
Cefepime is a zwitterion
with no net ionic charge. Its chemical configuration of associated with
high water solubility and rapid penetration through the outer membrane
of Gram-negative bacteria via negatively charged porin channels,
allowing for rapid achievement of high concentrations in the periplasmic
space. This penetration is necessary to gain access to the target sites,
the penicillin-binding proteins. In contrast, ceftazidime penetrates at
a very slow rate.
-
Cefepime has a high affinity
for penicillin-binding proteins 2 and 3, compared to ceftazidime, which
enhances the killing ability.
-
Cefepime has a lower
affinity for beta-lactamases than other extended-spectrum cephalosporins,
particularly the class I enzymes produced by nosocomial bacteria such as
Enterobacter spp. and Pseudomonas aeruginosa.
-
Cefepime is a weak inducer
of beta-lactamase, whereas ceftazidime is a strong inducer. With class I
beta-lactamases, strong inducers lead to hyperproduction and the
development of resistance during therapy.
-
Cefepime can be given every
12 hours, compared to every 8 hours with ceftazidime and every 6 hours
with cefotaxime. This is true for all indications, with the exception of
febrile neutropenia, in which the dosing interval for cefepime is every
8 hours. Overall, this should lead to a reduced workload for both
Nursing and Pharmacy.
-
Because ceftazidime slowly
penetrates the Gram-negative cell wall and slowly accumulates in the
bacterial periplasmic space, this allows time for the common beta-lactamases
(TEM and SHV enzymes) to mutate by substituting one or more amino acids
in the protein chain of the enzyme. This change results in a mutation of
the enzyme to an extended-spectrum beta-lactamase (ESBL). ESBLs are
capable of hydrolyzing a wide variety of beta-lactam antibiotics,
including the extended-spectrum cephalosporins and penicillins (e.g.,
piperacillin and ticarcillin). This is a particular problem with
Klebsiella pneumoniae, which had a 9% resistance rate at University
Hospital in 1998. The literature indicates that ceftazidime is the main
offender relative to ESBL inducement. While not as strong, cefotaxime
has also been implicated in ESBL inducement.
Table 1. Cephalosporin Formulary Conversion - Adults
|
Medication Prescribed |
Special Considerations |
Formulary Change |
| Ceftazidime 1 g q8h |
-- |
Cefepime 1 g q12h* |
| Ceftazidime 2 g q8h |
-- |
Cefepime 2 g q12h |
| Ceftazidime 2 g q8h |
Febrile neutropenia
|
Cefepime 2 g q8h |
| Ceftazidime 2 g q8h |
P. aeruginosa
meningitis |
No change - Ceftazidime used on non-formulary
basis |
| Ceftazidime 2 g q8h |
Non-pseudomonal gram
(-) meningitis |
Ceftriaxone 2 g q12h |
| Cefotaxime 1 g q6h |
-- |
Cefepime 1 g q12h |
| Cefotaxime 2 g q6h |
-- |
Cefepime 2 g q12h |
| Cefotaxime 2 g q4-6h
|
Empiric meningitis
treatment |
Ceftriaxone 2 g q12h |
*Dosage adjustments are required for cefepime in renal
failure (CrCl < 60 ml/min).
Table 2. Cephalosporin Formulary Conversion - Pediatrics
|
Medication Prescribed |
Special Considerations |
Age |
Formulary Change |
| Ceftazidime
or cefotaxime |
-- |
2 months – 16 years (<40 kg) |
Cefepime 50 mg/kg q12h (not to exceed adult dose) |
| Ceftazidime |
Febrile neutropenia OR cystic fibrosis |
2 months – 16 years (<40 kg) |
Cefepime 50 mg/kg q8h (not to exceed adult dose) |
|
Cefotaxime 200 mg/kg/day divided q6h |
Suspected or documented meningitis |
Pre-term to <1 month |
No change - Cefotaxime used on non-formulary
basis |
|
Cefotaxime 200 mg/kg/day divided q6h |
Suspected or documented meningitis |
1-2 months |
Ceftriaxone 100 mg/kg/day divided q12h |
|
Ceftazidime 100-150 mg/kg/day divided q8h |
Suspected or documented P. aeruginosa |
<2 months |
No change - Ceftazidime used on non-formulary
basis |
Both ceftazidime and cefotaxime appear to be responsible
for inducing the class I chromosomal beta-lactamases into a
hyperproduction state, which leads to resistance during therapy. This
problem is seen clinically in isolates of Enterobacter spp. and
Pseudomonas aeruginosa. At University Hospital in 1998, 31% of
Enterobacter cloacae isolates and 19% of Pseudomonas aeruginosa
were resistant to ceftazidime. This type of resistance leads to
cross-resistance to other extended-spectrum cephalosporins, penicillins,
and aztreonam. In addition to the above benefits, the manufacturer of
cefepime has offered a lower acquisition price. This low price, coupled
with a twice-daily dose, will offer our hospital considerable cost
savings. Pharmacy will call prescribers upon receipt of an order for
ceftazidime or cefotaxime, inquire about the indications for use, and
identify appropriate formulary alternatives. NOTE: Formulary status of
ceftriaxone has not changed.
Prepared by: Bob Rapp, Pharm.D., FCCP
Associate Director of Pharmacy
|
|
_________________________________________________________________________________________________________
Approved by P&T
Committee: 6/99
|
Posted on: 8/02
|
For Internal University of Kentucky Chandler Medical Center Use Only
Comments to
Kelly Smith, Pharm.D.,
Last Modified:
August 13, 2006
Copyright © 2002, University of Kentucky Chandler Medical Center
Terms,
Conditions & Privacy Statement |
