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Antimicrobial Agents and Chemotherapy, September 2001, p. 2643-2647, Vol. 45, No. 9
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2643-2647.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Stability and Compatibility of Ceftazidime
Administered by Continuous Infusion to Intensive Care
Patients
Hélène
Servais* and
Paul M.
Tulkens
Unité de Pharmacologie Cellulaire et
Moléculaire, Université catholique de Louvain, Brussels,
Belgium
Received 23 October 2000/Returned for modification 11 March
2001/Accepted 5 June 2001
 |
ABSTRACT |
The stability and compatibility of ceftazidime have been examined
in the context of its potential use in concentrated solutions for
continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route. Ceftazidime stability in 4 to 12% solutions was found
satisfactory (<10% degradation) for 24 h if kept at a
temperature of 25°C (77°F) maximum. Studies mimicking the
simultaneous administration of ceftazidime and other drugs as done in
clinics showed physical incompatibilities with vancomycin, nicardipine,
midazolam, and propofol and a chemical incompatibility with
N-acetylcystein. Concentrated solutions (50 mg/ml) of
erythromycin or clarithromycin caused the appearance of a precipitate,
whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole,
ketamine, sufentanil, valproic acid, furosemide, uradipil, and a
standard amino acid solution were physically and chemically compatible.
| |
TEXT |
In their original review, Craig and
Ebert (7) pointed out to the many potential advantages of
the administration of 
-lactams by continuous infusion (optimization
of outcome based on their pharmacodynamic properties [time-dependent
antibiotics {5, 6}] as well as pharmacoeconomic
advantages [decrease in the amount of drug which needs to be
administered each day and reduction of nursing workload
{21}]). Yet, because -lactams are known to be
unstable in aqueous media (intrinsic fragility of the -lactam ring),
particular attention must be paid to the practical conditions of this
type of administration. -Lactam antibiotics are also known to be
chemically and physically incompatible with many other drugs. Even
though several authors have examined the stability and degradation of
ceftazidime in aqueous solutions, sometimes specifically in view of its
potential use by continuous infusion (8, 10, 11, 18, 26, 28-30,
34, 37), none of them has specifically tested the potential
temperatures and concentrations that may be encountered in the
treatment of intensive care patients. The same consideration applies
also largely to the problem of drug incompatibilities, although useful
information has already been assembled in this context (2, 14,
16, 23, 31, 33). The present study was therefore initiated to
specifically and critically assess the stability and compatibility of
ceftazidime within the context of its potential use by continuous
infusion for patients hospitalized in intensive care units for severe
nosocomial pneumonia. We selected ceftazidime for normative studies,
since this third-generation cephalosporin has a well-established
efficacy in empirical therapy for this type of patient
(9). Moreover, pharmacokinetic studies have indicated that
a stable concentration of ~20 mg/liter in serum can be reached using
acceptable daily doses (~4 g) of ceftazidime in humans (17,
21).
Overall design of study and methods.
We wanted to mimic as
closely as possible a projected routine use of ceftazidime. Successful
therapy was considered to require a stable serum drug concentration of
25 mg/liter, i.e., above most accepted breakpoints for ceftazidime,
which can be achieved with a daily infusion of 6 g/day. This would also
yield an area under the concentration time curve from 0 to 24 h of
600 mg × h/liter (which some studies have ruled optimal
for -lactams when considering organisms for which the MIC is up to 4 mg/liter [25]) and would also be within the the limits
of the registered daily dosages of ceftazidime in most countries.
Clinical usage dictated that this amount of drug be administered from a
single 48-ml syringe (as used in most conventional infusion pumps)
maintained at room temperature and changed only once daily (to minimize
handling risks and costs). Finally, the intravenous line might need to be used for simultaneous administration of other parenteral drugs commonly needed for patients with severe, life-threatening nosocomial pneumonia.
All solutions of ceftazidime were prepared using the branded product
distributed for hospital usage in Belgium and contained up to 6 g
of ceftazidime per 48 ml. The pH of the solutions was ~7.4, and
unless stated otherwise, no adjustment of pH was made. After the
solutions had been maintained at appropriate temperatures for the
necessary lengths of time, the ceftazidime content of the solutions was
determined by high-pressure liquid chromatography (HPLC) in comparison
with freshly prepared standards (Lichrosorb 100RP-18 column [25 by 0.4 cm; 5-µm pore size; Merck KGaA, Darmstadt, Germany] with
Novapack C18 precolumn; isocratic elution with 10 mM sodium
acetate buffer [pH 4.0]; acetonitrile [89:11 vol/vol]; UV detector
[absorption wavelength, 254 nm]; range of linearity, 0 to 400 µg/ml
[r2 = 0.999]; and quality control samples
with each series of assay [maximum deviation, 5%; intraday and
interday coefficients of variation, ~0.3 and ~5%, respectively]).
Stability was considered satisfactory if the ceftazidime content
remained within 90% of its original value at any time point
(1). Degradation products were detected and characterized
by HPLC analysis coupled with mass spectrometry (Finnigan LCQ mass
spectrometer, Thermoquest, San Jose, Calif., with an Electrospray
ionization and data processing with Xcalibur software), as well as by
cochromatography with genuine samples of the putative degradation
products when available.
Compatibility was tested by mixing ceftazidime at its maximally
projected concentration (~12% [wt/vol]) and each potentially
coadministered drug (at the highest commercially available or
clinically used concentration) in a volume ratio corresponding
to their
respective projected flow rates (2 ml/h for ceftazidime
and the flow
rate compatible with the highest accepted daily dosage
and schedule of
administration of each of the other drugs, as
routinely performed in
our clinical environment [Table
1]).
All
drugs were obtained and used under the pharmaceutical form
distributed
in Belgium for parenteral use by or on behalf of the
original
marketing authorization holder. Physical compatibility was
assessed
by the naked eye for signs of precipitation or other evidence
of alteration (repeated mirroring) followed by independent,
professional
examination using an Allen LV28 Liquid Viewer (P. W. Allen & Co.
Ltd., Tewkesbury, United Kingdom) operated with two
polarizing
filters. Chemical compatibility was assessed by determining
the
ceftazidime content by HPLC, followed by thin-layer chromatography
if a decrease of the ceftazidime content of
10% was detected
in HPLC
without the simultaneous appearance of an identifiable
new compound or
of a ceftazidime degradation product. The chemical
intactness of the
accompanying drug has not been tested systematically.
For compounds
administered in a short period of time, indeed,
the molar ratio of each
drug to ceftazidime was usually much greater
than 1, making a
loss of ceftazidime a more accurate means of
evidencing a chemical
reaction between them. The intactness of
the aminoglycosides was,
however, systematically examined, since
interaction between these drugs
and
-lactams has been documented
(
22). No evidence of
degradation was noted, using an automated
fluorescence polarization
immunoassay (Abbott TdX system, Abbott
Laboratories, Abbott Park, Ill.;
Dainabot Co. Ltd., Tokyo, Japan)
with standards prepared in the same
vehicle as the samples for
constructing the calibration curves
(intraday coefficient of variation,
<5%; all assays were done in 1 day). Concerning compounds administered
over a 24-h period and for
which no physical instability was detected,
available pharmaceutical
information indicated no interaction
with ceftazidime
(
31).
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TABLE 1.
Drugs, conditions, and results of compatibility studies
mimicking the coadministration of ceftazidime with other drugs
through the same line of infusiona
|
|
Stability of ceftazidime in concentrated solutions.
Figure
1 shows the stability of ceftazidime when
incubated at increasing temperatures for up to 24 h (Fig. 1A), at
concentrations up to 12% (wt/vol) (Fig. 1B), and at pH values ranging
from 6 to 12 (Fig. 1C; exposure of ceftazidime to a pH of 
4 resulted in immediate precipitation). Taking 90% stability as a limit, it
clearly appears that ceftazidime must be kept at temperatures not
higher than 25°C, whatever its concentration in the 4 to 12% (wt/vol) range. As reported earlier, the pH of the solutions appeared critical and could not exceed 10 even at 4°C (the pH of a freshly prepared solution lies between 7.1 and 7.7). Upon dissolution, all
ceftazidime preparations displayed a pale yellow when their concentrations exceeded 8%. Only a minor increase in color intensity (to light yellow) was noted in samples kept at 25°C for 24 h. In
contrast, samples brought to 37°C or higher progressively turned reddish and, thereafter, reddish-brown over time while giving rise to a
definite sulfide odor. This sets up a definite limit in the application
of the continuous infusion approach with ceftazidime not clearly
evidenced from previous studies.
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FIG. 1.
Stability of ceftazidime at various temperatures. (A)
Influence of the time of incubation (12% solution); (B) influence of
the drug concentration (24-h incubation); (C) influence of the pH (12%
solution; 24-h incubation) (std, unincubated samples). All values are
the mean of three independent determinations ± standard
deviations (symbols without bars correspond to values for which the
standard deviation is smaller than the symbol size). w/v, wt/vol.
|
|
Identification of ceftazidime degradation products and mechanism of
ceftazidime degradation.
After maintaining a sample of ceftazidime
(12%) at 40°C for 70 h, we could positively identify the
appearance of [(2-amino-4-thiazolyl) (1-carboxy-1-methylethoxy)
imino] acetyl-ethanal and of pyridine (both detected also in
small amounts at 25°C) as well as of the 
-2 isomer of ceftazidime
(data not shown). This suggests a dual degradation pathway, largely
dependent on the temperature and partly involving the opening of the
-lactam ring as illustrated in Fig. 2.
Base catalysis by water, as well as electrophilic as well as
nucleophilic attacks (on the carbonyl and on the nitrogen of the
-lactam ring, respectively), are probably responsible for this
degradation, as shown with several penicillins and cephalosporins (3, 12, 19, 20, 32, 35, 36). Opening of the -lactam ring is considered dangerous in the case of pencillins since the resulting penicilloic acids easily react with albumin to cause the
formation of potent allergenic haptens (4, 27). Yet the actual concentrations of the corresponding open-ring derivative of
ceftazidime (exomethylene derivative) will be vanishingly small because
this compound is very unstable, and this should, in the case of
ceftazidime, minimize the risk of hapten formation. No toxicological
data, however, are available for the [(2-amino-4-thiazolyl) (1-carboxy-1-methylethoxy) imino] acetyl-ethanal. Finally, the amount
of pyridine liberated will remain lower than the USP limit of 1.1 mg/ml
for pharmaceutically acceptable ceftazidime solutions (based on
published data showing that a 10% degradation of ceftazidime in a
5.8% solution over 24 h is associated with the liberation of only
~0.5 mg of pyridine/ml [26]). The total amount which could be passed on to a patient will, therefore, be 800 to 1,000-fold lower than the published median lethal doses for either oral or subcutaneous administration of pyridine to rats (24; see
also http://physchem.ox.ac.uk/MSDS/P/pyridine.html).
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|
FIG. 2.
Degradation pathways of ceftazidime as determined by
HPLC-mass spectrometry and cochromatography studies of 12% (wt/vol)
samples maintained at various temperatures for up to 70 h. The
opening of the -lactam ring occurs through the formation of an
exomethylene derivative (with a free carboxylate function), which is
then converted into the [(2-amino-4-thiazolyl)
(1-carboxy-1-methylethoxy) imino] acetyl-ethanal (13).
|
|
Compatibility studies.
Table 1 shows that all four
aminoglycosides, fluconazole, ketamine, sufentanil, valproic acid,
furosemide, uradipil, and the standard amino acid solutions (VAMIN)
were all found physically and chemically compatible as far as
ceftazidime was concerned (for aminoglycosides, we also checked for
intactness of these drugs and found no evidence of significant effect
after 1 h of contact at 25°C; this lack of
aminoglycoside-ceftazidime interaction, in spite of reports pointing to
aminoglycoside--lactam incompatibilities [15, 22]
probably stems from our mimicking of the practical conditions of their
coadministration, i.e., a rapid infusion of the aminoglycoside,
consistent with its now widely accepted once daily schedule
[13]). In contrast, erythromycin and clarithromycin generated a precipitate when used at high concentration (50 mg/ml). Drugs incompatible for physical reasons most notably included vancomycin (even if diluted [33]), midazolam
(31), nicardipine, and propofol (the latter
incompatibility was due to ceftazidime being trapped in the
phospholipid emulsion [INTRALIPD] in which propofol is supplied; this
incompatibility was not observed in conventional compatibility studies
[31]). N-Acetylcystein caused a linear
decrease of the ceftazidime content at a rate of ~20% per h at
25°C. Additional studies using other sulfhydril donors suggested this
decrease to most likely result from a thiol-dependent attack of ceftazidime.
In conclusion, the data presented here have validated the potential use
of ceftazidime by continuous infusion with regard
to the pharmaceutical
point of view and ceftazidime's application
in patients who are
hospitalized in intensive care units and are
receiving drugs commonly
used for the overall management of severe
nosocomial pneumonia. It also
sets the limits of the approach
in terms of temperature and
coadministration of specific drugs.
We suggest that any drug not listed
here should be studied in
detail before its coadministration with
ceftazidime can be considered
safe. Our studies cannot be extended
without regard to other
-lactams.
Although all of them basically
show a similar chemical instability,
meaningful differences can
nevertheless be observed between individual
molecules. Compatibility of
individual
-lactams with other drugs
may also be markedly dependent
on the nature of their side chains,
making general recommendations
hazardous. Thus, beyond its informative
aspect concerning ceftazidime,
the present study should perhaps
be also viewed as normative for other
-lactams as well as for
other specific clinical conditions in which
administration of
antibiotics by continuous infusion may be rationally
envisioned.
| |
ACKNOWLEDGMENTS |
M. P. Mingeot-Leclercq provided general guidance in our studies, E. de Hoffmann and B. Rollmann (Université catholique de Louvain,
Louvain-la-Neuve, and Brussels, Belgium) provided essential help in our
analytical studies, and E. Dussart (SmithKline Biologicals Manufacturing S.A., Rixensart, Belgium) provided professional assessment of drug physical compatibility. F. Renoird-Andries and R. Rozenberg gave technical assistance.
This work was supported by the Belgian Fonds National de la Recherche
Scientifique (grant no. 3.4516.94).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Unité de
Pharmacologie Cellulaire et Moléculaire, Université
catholique de Louvain, UCL 73.70 avenue E. Mounier 73, B-1200 Brussels,
Belgium. Phone: 32-2-764.73.56. Fax: 32-2-764.73.73. E-mail:
Helene.Servais{at}facm.ucl.ac.be.
| |
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Antimicrobial Agents and Chemotherapy, September 2001, p. 2643-2647, Vol. 45, No. 9
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2643-2647.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Baririan, N., Chanteux, H., Viaene, E., Servais, H., Tulkens, P. M.
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Viaene, E., Chanteux, H., Servais, H., Mingeot-Leclercq, M.-P., Tulkens, P. M.
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