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Antimicrobial Agents and Chemotherapy, May 1998, p. 1093-1097, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparison of Concentrations of
Sulbactam-Ampicillin Administered by Bolus Injections or Bolus plus
Continuous Infusion in Tissues of Patients Undergoing Colorectal
Surgery
Claude
Martin,1,*
Agnès
Cotin,2
Annick
Giraud,1
Mireille
Beccani-Argème,1
Pierre
Alliot,3
Marie-Noëlle
Mallet,2 and
Maxime
Argème3
Department of Anesthesia and Intensive Care,
Nord Hospital, Marseilles University Hospital System and Marseilles
Medical School,1
Microbiology
Department, Salvator Hospital,2
and
Surgical Departement, Nord
Hospital,3 Marseilles, France
Received 26 February 1997/Returned for modification 16 September
1997/Accepted 10 February 1998
 |
ABSTRACT |
The concentrations of sulbactam and ampicillin were determined in
sera and different abdominal tissues of 16 patients who underwent
elective colorectal surgery. Patients were randomly allocated to two
groups. At the time of induction of anesthesia, patients in group 1 (eight patients) were given 1,000 mg of sulbactam with 2,000 mg of
ampicillin by intravenous bolus injection (3 min). This dose was
administered again after 2 h by bolus injection by the same route.
Patients in group 2 (eight patients) were given the same initial dose
of sulbactam-ampicillin by bolus injection (3 min). Then, a continuous
infusion of 1,000 mg of sulbactam with 2,000 mg of ampicillin in normal
saline was immediately started and was administered over a 4-h period.
Blood samples were collected to determine peak (10 min) and trough (end
of surgery) antibiotic levels. Serial blood samples were also collected
at predetermined periods (at the time of opening and closing of the
abdominal cavity and at the time of surgical anastomosis). Abdominal
wall fat, epiploic fat, and colonic wall tissue samples were collected
simultaneously. Antibiotic concentrations were determined by
high-performance liquid chromatography. Similar levels of the drugs in
serum were observed for the two regimens of administration, with trough
sulbactam levels of 33 ± 16 and 37 ± 22 µg/ml in groups 1 and 2, respectively, and trough ampicillin levels of 72 ± 55 and
79 ± 47 µg/ml in groups 1 and 2, respectively. Similar
sulbactam concentrations were observed in abdominal tissues whichever
regimen of administration was used; in fatty tissues the sulbactam
concentrations ranged from 2.7 to 3.8 µg/g for group 1 and from 1.7 to 4.0 µg/g for group 2, and sulbactam concentrations in the colonic
wall were 5.6 ± 7.7 and 6.8 ± 3.2 µg/g in groups 1 and 2, respectively (not significant). Again, no influence of the regimen of
administration was observed on tissue ampicillin concentrations; in
fatty tissues ampicillin concentrations ranged from 4.1 to 5.4 µg/g
for group 1 and from 3.2 to 5.8 µg/g for group 2, and sulbactam
concentrations in the colonic wall were 7.0 ± 2.8 and 11.0 ± 4.7 µg/g for groups 1 and 2, respectively (not significant). In
most patients, the concentrations of ampicillin-sulbactam were greater
than the MIC at which 50% of isolates are inhibited
(MIC50) for Bacteroides fragilis in the fatty
tissues. In the colonic wall, for most patients the concentrations of
ampicillin-sulbactam were greater than the MIC90 for
B. fragilis. No influence of the regimen of administration was observed on the ratio of the two components in the tissues investigated and in sera. In conclusion, a second intraoperative bolus
injection or a continuous infusion were equally effective in
maintaining sulbactam-ampicillin concentrations in abdominal tissues.
The first method of administration can be recommended since it is
easier to handle.
| |
INTRODUCTION |
Colorectal surgery is a contaminated
aseptic type of surgery, and prophylactic antibiotics are widely used
prior to and during surgery. The importance of the prophylactic
antibiotics in reducing postoperative infections and mortality has been
demonstrated (4, 15, 22). Antibiotics are selected on the
basis of their ability to eradicate the bacteria most likely to
contaminate a surgical wound: Escherichia coli and various
members of the family Enterobacteriaceae, Enterococcus
faecalis, Staphylococcus aureus, Bacteroides
fragilis, and other anaerobic bacteria (4, 15, 22). The
basic concept underlying the optimal use of antibiotic prophylaxis is
that an adequate amount of an appropriate antibiotic should be present in the blood and tissues before a bacterial challenge. It seems clear
that during a surgical procedure, adequate antibiotic concentrations should be achieved at all sites of potential infection. Also, antibiotic activity should be maintained throughout the procedure, from
incision to closure (7, 9, 18, 19). The combination of
sulbactam-ampicillin can be selected for use as a prophylactic antibiotic in abdominal surgery (10, 11, 23). It is
effective in the prevention of wound infections in operations in which
the most likely pathogens are gram-negative, anaerobic, or mixed
bacteria (20). However, sulbactam-ampicillin has a short
half-life (1 h) (8, 12), and for longer procedures such as
colorectal surgery, antibiotic concentrations may not be maintained
until the end of surgery when the first bolus dose is administered at the time of induction of anesthesia (7, 18, 19). When
intermittent antibiotic dosing is used, antibiotic levels in serum and
tissues will gradually decrease and the bacteria will often be exposed to low concentrations during the dosing interval. The present study was
conducted during colorectal surgery to compare the antibiotic activities of two different regimens of intraoperative antibiotic administration: the use of a second bolus injection 2 h after the
beginning of surgery or the use of a continuous antibiotic infusion
during surgery. We wanted to confirm the maintenance of antibacterial
concentrations of the antibiotics at potential sites of infection.
| |
MATERIALS AND METHODS |
Patients and drugs.
This study received the approval of the
ethical committee of our institution (Hopital Nord), and all patients
gave their informed consent. Fifteen patients were scheduled for
elective colorectal surgery. All patients had normal hepatic function
(serum bilirubin level, <10 µmol/liter) and renal function
(creatinine clearance, >100 ml/min/1.74 m2). None had a
history of allergic reaction to 
-lactam antibiotics. None presented
with any clinical sign (normal body temperature, normal physical
examination) or laboratory sign (normal leukocyte count) of infection
or had received antibiotic treatment in the preceding 3 weeks. Patients
were randomly assigned to one of two groups. Patients in group 1 (five
males and three females; mean age, 57 ± 12 years; mean body
weight, 65 ± 10 kg) were given 1,000 mg of sulbactam with 2,000 mg of ampicillin by intravenous bolus injection (3 min). This dose was
administered again after 2 h. Patients in group 2 (six males and
two females; mean age, 59 ± 14 years; mean body weight, 67 ± 11 kg) were given by intravenous bolus injection (3 min) the same
initial dose of sulbactam-ampicillin used for group 1 patients, and a
continuous infusion of 1,000 mg of sulbactam with 2,000 mg of
ampicillin in normal saline was immediately started and administered
over a 4-h period.
Specimen collection.
Blood samples (10 ml each) were
collected from a central venous catheter before surgery, 10 min after
the beginning of surgery (peak level), and at the end of surgery
(trough level). Blood samples were kept on ice and were centrifuged in
a refrigerated centrifuge within 30 min of collection. Sera were placed
in polypropylene tubes. Several samples of the selected tissues were
collected during surgery. Abdominal wall fat and epiploic fat were
obtained at the times of opening and closure of the abdominal cavity;
colonic wall and epiploic fat samples were obtained at the time of
surgical anastomosis. The exact time of sample collection was
registered, and a corresponding blood sample was taken. Tissue sample
sizes were 1 cm3 or larger. To remove the attached blood,
all tissue samples were rinsed in sterile saline and were cleaned with
dry, sterile gauze. Tissue samples were placed in sterile polypropylene
tubes. Serum and tissue samples were assayed immediately following
surgery.
Specimen preparation procedures.
For determination of
sulbactam levels in serum, 1 ml of the sample was mixed with 0.5 ml of
imidazole (2.5 M; pH 6.8) (5, 21). The solution was stored
for 24 h at 4°C. After mixing (with a Vortex mixer for 30 s) the sample was deproteinized by the addition of 2.0 ml of
acetonitrile. After mixing (15 s) and centrifugation at 3,000 rpm
(Sorvall centrifuge) for 10 min, acetonitrile was removed by extraction
with 3.0 ml of dichloromethane. Then, the solution was vortexed (30 s)
and centrifuged at 3,000 rpm (Sorvall centrifuge) for 5 min. The
aqueous phase (50 µl) was injected onto the high-performance liquid
chromatography (HPLC) system.
For determination of ampicillin levels in serum, 1 ml of the sample was
mixed with 1 ml of acetonitrile. After mixing and centrifugation the
sample was then treated in the same way that the sulbactam samples
were. The aqueous phase (50 µl) was injected onto the HPLC system.
For determination of the sulbactam and ampicillin levels in the
tissues, the samples were weighed and 500 mg was homogenized with an
Ultra-Turrax homogenizer at 4.0°C for 45 s. One milliliter of
distilled water was used for the tissue homogenization process. Centrifugation of the homogenate yielded a clear supernatant which was
treated like serum samples were.
HPLC systems.
The sulbactam concentrations were determined
by using a dual-column HPLC system with UV detection (5,
21). The precolumn (LiChrospher RP 18 E, 5 mm; 25 by 4 mm [inner
diameter]) was connected to the analytical column (LiChrospher RP 18 E, 5 µm; 125 by 4 mm [inner diameter]). The mobile phase consisted
of 2% acetonitrile and 98% 0.1 M potassium phosphate buffer (pH 6.1).
The flow rate was 1.0 ml/min, and sulbactam was detected at 322 nm.
The ampicillin concentrations were determined by using the same HPLC
systems described above. The mobile phase consisted of
5% acetonitrile
and 95% 0.01 M potassium phosphate buffer (pH
4.7). The flow rate was
1.6 ml/min, and ampicillin was detected
at 219 nm. The lower limit of
detection of sulbactam and ampicillin
was 0.1 µg/ml for tissue and
serum samples. The percent recoveries
for sulbactam were 89% ± 4%
and 91% ± 3% for serum and tissue
samples, respectively. The percent
recoveries for ampicillin were
94% ± 2% and 93% ± 4% for serum
and tissue samples, respectively.
For sulbactam, the within-day and
between-day (3 days) interassay
precisions were 1.43 and 1.41% (20 µg/ml) and 2.79 and 2.77% (40
µg/ml) for serum samples,
respectively, and 3.3 and 5.0% (3 µg/g)
and 4.2 and 6.4% (0.5 µg/g) for tissue samples, respectively.
For ampicillin the within-day
and between-day (3 days) interassay
precisions were 1.46 and 1.20% (25 µg/ml) and 1.77 and 1.24% (50
µg/ml) for serum samples,
respectively, and 3.7 and 5.2% (15 µg/g)
and 5.3 and 6.7% (1 µg/g) for tissue samples, respectively.
Evaluation of sulbactam:ampicillin ratios.
Samples of
specific tissues were analyzed according to collection time: opening
and closure of the abdominal cavity and surgical anastomosis of the
colon. For each defined period, the ratios of the concentrations of the
two compounds (sulbactam and ampicillin) were obtained for the
different tissue samples and the corresponding serum samples. The
mean ± the standard deviation ratio was calculated for both
groups. Antibiotic concentrations in tissues were also compared to the
MICs at which 50% (MIC50s) and 90% (MIC90s)
of Bacteroides fragilis isolates are inhibited (2 and 8 mg/liter for sulbactam and ampicillin, respectively), assuming a 1:2
sulbactam-to-ampicillin ratio.
Clinical evaluation.
All patients were closely monitored
during their hospital stays and for up to 30 days for clinical or
laboratory signs of infection.
Statistical analysis.
Statistical analysis was performed by
Student's t test for unpaired values and the chi-square
test. A P value of less than 0.05 was considered
significant.
| |
RESULTS |
Concentrations in serum.
The sulbactam and ampicillin
concentrations in serum are presented in Table
1. No significant differences in
concentrations in serum were observed, whichever drug regimen used. At
the end of surgery both methods of drug administration achieved high
levels of sulbactam and ampicillin in the two groups.
Antibiotic concentrations in tissues.
The sulbactam and
ampicillin concentrations in tissues at various periods during surgery
are presented in Table 2. Stable concentrations of antibiotics were observed in fatty tissues when the
concentrations at the surgical opening and closure periods are
compared. This was observed after administration of a second bolus dose
or the use of the continuous infusion during surgery. No significant
differences were observed between the two groups. Sulbactam and
ampicillin concentrations were higher in the colonic wall than in fatty
tissues. The mode of antibiotic administration during surgery had no
influence on the concentrations achieved in colonic wall samples.
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TABLE 2.
Concentrations of sulbactam and ampicillin in abdominal
tissues and serum of patients undergoing colorectal surgery at
different periods of the surgical procedure
|
|
Sulbactam-to-ampicillin concentration ratios.
The
sulbactam-to-ampicillin concentration ratios are presented in Tables 1
and 3. For group 1, they ranged from 0.33 to 0.70 in tissues and from 0.44 to 0.67 in serum. For group 2, the ratios ranged from 0.41 to 0.69 in tissues and from 0.46 to 0.67 in
serum. The ratios were not significantly modified by the method of
administration of antibiotics during surgery.
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TABLE 3.
Sulbactam concentration/ampicillin concentration ratios
at different periods of the surgical procedure in patients undergoing
colorectal surgery
|
|
Table
4 presents data for the patients
who achieved ampicillin-sulbactam concentrations in tissue greater than
the MIC for
B. fragilis. For most patients concentrations in
the fatty tissues
greater than the MIC
50 were achieved, but
only in the colonic
wall were concentrations greater than the
MIC
90 for
B. fragilis achieved.
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TABLE 4.
Numbers of patients with concentrations in tissue greater
than or equal to the MIC50 and MIC90 for
B. fragilis at the different periods of the
surgical procedure
|
|
No patient had any signs of postoperative infection during the 30-day
follow-up period.
| |
DISCUSSION |
This study shows that the intraoperative administration of
sulbactam-ampicillin as two sequential bolus injections or by bolus injection plus a continuous infusion during surgery had no significant influence on antibiotic penetration into tissue. Previous studies have
established the basic principles of antibiotic prophylaxis in surgical
procedures, and the main points are that (i) the antibiotic must reach
the tissues involved before surgery allows bacterial contamination, and
(ii) the drug must attain and maintain concentrations in serum and
tissues high enough to inhibit the growth of contaminating pathogens
(7, 9, 15, 22). This study addressed the tissue penetration
of a -lactam--lactamase inhibitor combination, with the drugs
being administered as two sequential bolus injections or one bolus
injection immediately followed by a continuous infusion during the
intraoperative period. The absolute concentrations of the drugs in
tissues, the time course of these concentrations, and the extent of
penetration are of interest. Penetration was evaluated by measuring the
concentration in tissue-to-concentration in plasma ratios at specific
collection times. The data for sulbactam and ampicillin are in
agreement with results reported previously (11, 13, 14).
Specific differences between tissues were observed. The extent of
sulbactam and ampicillin penetration into fat was 4 to 8% of the
levels in serum, significantly lower than the penetration into the
colonic wall (10 to 20%; P < 0.02). This is in
agreement with a study on the penetration of tazobactam-piperacillin into fat, which was 10% of the levels in plasma (16), but
is at variance with a study with clavulanic acid-amoxicillin, in which
the former drug had a higher level of penetration (30%) than the
latter drug (10 to 20%) (17). The exact mechanisms that
cause these important findings deserve further investigations. The
level of penetration of sulbactam and ampicillin into the colonic wall
was higher than that into fatty tissues. This might be explained by the
fact that the blood flow to the gastrointestinal tract is higher than
that to the fat. From these data, it is clear that no single mechanism
governs the extent of penetration of antibiotics into tissues. Further
investigations are needed to more clearly define the relationship among
blood flow, water content, and the physicochemical properties of the
agents.
In the present study, the extent of penetration of both compounds
(sulbactam and ampicillin) was maintained throughout the surgical
procedure thanks to the intraoperative administration of the
antibiotics. In clinical practice, when intermittent antibiotic dosing
is used, antibiotic levels in serum and tissues will gradually decrease. The bacteria will often be exposed to low concentrations of
the antibiotic during the dosing interval and infection may start in
the tissues potentially affected by postoperative infection. This
emphasizes the need for repeated administration of drugs with shorter
half lives (7, 15, 17, 22), such as sulbactam and ampicillin
(8, 12). If the intraoperative administration is not
performed, decreased concentrations of both compounds, sulbactam and
ampicillin, would probably be measured in fatty tissues and colonic
wall, with an increased risk of postoperative infection. To maintain
active concentrations of antibiotics, one can consider either the
administration of a second intraoperative bolus injection or continuous
administration during surgery. The administration of an intraoperative
bolus dose (after 2 h, which corresponds to two half-lives for
most antibiotics used) is recommended, but objective data are lacking
(7, 15, 22). -Lactam antibiotics can also be administered
by continuous infusion (6), and in the present study, both
routes of administration were compared. With either route, the same
concentrations in serum (including trough levels), the same antibiotic
concentrations in tissues, the same concentration in
tissue/concentration in serum ratios, and the same
sulbactam-to-ampicillin concentration ratios were achieved. Thus, both
administration regimens were equally effective at preventing
fluctuating antibiotic concentrations during colorectal surgery. Since
the administration of a second intraoperative dose is easier to handle
than a continuous infusion, the former route of administration can be
selected for clinical use.
Current practice with -lactam--lactamase inhibitor combinations
is to maintain an optimal ratio between the two components (1:2
sulbactam to ampicillin) (3). Because of their similar pharmacokinetics these two components theoretically maintain a 1:2
ratio at the site of potential infection over the entire period of
surgery. In the present study, ratios close to 1:2 were obtained in the
tissues studied, but it has been suggested that the efficacy of
sulbactam-ampicillin is more dependent upon the maintenance of both
sulbactam and ampicillin levels above a minimum critical concentration
than on the maintenance of a constant 1:2 ratio (2). With
both regimens of antibiotic administration used in the present study,
the levels of sulbactam and ampicillin were maintained in the studied
tissues until the end of surgery. Will these concentrations be active
against the most common pathogens encountered during surgery? It can be
speculated that a desirable goal is to achieve antibiotic levels above
the MIC for the potential pathogen. This also means maintaining such
levels until the end of the surgical procedure (7, 19). At
the time of closure of the abdomen, sulbactam concentrations in the
fatty tissues reached an average of 2 µg/g. At this concentration of
sulbactam, the ampicillin MIC for plasmid-mediated
-lactamase-producing strains of E. coli can be as high as
16 µg/ml (1). Given the average level of ampicillin
achieved in the same tissues (Table 2), some patients can be at risk of
postoperative infection. This finding was observed whatever the regimen
of antibiotic administration used. With regard to B. fragilis, in most patients, antibiotic levels greater than the
MIC50 were achieved in the fatty tissues up to the end of
surgery, but only in the colonic wall were antibiotic concentrations
greater than the MIC90 for this organism achieved. From a
clinical point of view, in the present study no patient exhibited any
clinical or laboratory signs of postoperative infection during the
30-day follow-up period.
In conclusion, the results of this study indicate that the
intraoperative administration of sulbactam-ampicillin is able to maintain constant antibiotic levels in tissue during surgery. After the
administration of a first bolus injection 30 min prior to surgery,
antibiotic levels can be maintained either by the injection of a second
bolus dose after 2 h (two half-lives) or by the use of a
continuous infusion started immediately after administration of the
first bolus dose and administered over 4 h.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Département d'Anesthésie, Hôpital Nord, 13915 Marseille Cedex 20, France. Phone: 33-491-96-86-50. Fax:
33-491-96-28-18. E-mail: cmartin{at}ap-hm.fr.
| |
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Antimicrobial Agents and Chemotherapy, May 1998, p. 1093-1097, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
