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Sulbactam/Cefoperazone Versus Cefotaxime for the Treatment of
Moderate-to-Severe Bacterial Infections: Results of a Randomized, Controlled
Clinical Trial
Li Jia-tai, Lu Yuan, Hou Jie, Chen Yi-fang,
Miao Jing-zhi, Jia Yu-xia, Hou Jun, Zhang Xiu-zhi,
Chen Dong-ke, Hu Wen-zhi, Li Li-jin, Liu De-meng,
Wang Zhe, Wu Jin, Gu Jun-ming, Wang Hui-ling,
Zhang Yi-ling, and Sun Ling
From the Institute of Clinical Pharmacology, Beijing Medical
University, and Beijing Hospital, Beijing; 2nd Affiliated Hospital, Tian
Jin Medical University, Tian Jin; and 2nd Affiliated Hospital, Da Lian
Medical University, Da Lian, People's Republic of China
We conducted a randomized, open-label, controlled, multicenter study to compare sulbactam/
cefoperazone with cefotaxime in terms of efficacy and safety for the treatment of hospitalized patients
with moderate-to-severe bacterial infections. More than two-thirds of the pathogens recovered from
these patients produced /3-lactamase. Two hundred-seven (88.1%) of the 235 patients enrolled
completed the study and were included in the efficacy and safety evaluations. One hundred-three
patients received sulbactam/cefoperazone (2-4 g/d) administered in evenly divided doses every 12
hours by a 30-minute intravenous drip; 104 patients received cefotaxime (6-12 g/d) administered
in evenly divided doses every 6 or 8 hours by a 30-minute intravenous drip. The overall efficacy
rates (i.e., cure or markedly improved) were 95% for the sulbactam/cefoperazone group and 90%
for the cefotaxime group (P = .186), whereas the bacterial eradication rates were 85% for the
sulbactam/cefoperazone group and 81% for the cefotaxime group (P = .467). Both drug regimens
were well tolerated. Sulbactam/cefoperazone is effective and safe for the treatment of moderate-tosevere bacterial infections caused mainly by /3-lactamase—producing organisms.
Sulbactam/cefoperazone (Sulperazon; Pfizer Inc., New
York) is a synergistic antimicrobial combination with marked
in vitro antibacterial activity against a broad spectrum of organisms [1]. Sulbactam is a /3-lactamase inhibitor that can irreversibly inhibit several bacterial penicillinases and cephalosporinases produced by a variety of bacteria [2]. When combined
with a /3-lactam antibiotic, sulbactam can enhance the activity
of enzyme-resistant antibiotics [1-4].
The combination of sulbactam/ampicillin has been widely
used in the treatment of bacterial infections. When combined
with cefoperazone, sulbactam inhibits f3-lactamase -producing
isolates and thus significantly improves cefoperazone's activity
against gram-negative resistant bacilli, including highly resistant Enterobacteriaceae [4]. The activity of cefoperazone
against Staphylococcus aureus is greater than that of other
third-generation cephalosporins, and this activity is further
strengthened when cefoperazone is combined with sulbactam.
The "Guidelines for the Clinical Research of Antimicrobial Agents" of the
Ministry of Public Health, People's Republic of China, were followed in the
conduct of this study.
This article is part of a series of papers presented at a satellite symposium
to the Western Pacific Congress on Chemotherapy. The symposium was entitled "An Update on Cephalosporin Resistance and the Role of Sulbactam/
Cefoperazone" and was held in Manila in December 1994.
Reprints or correspondence: Dr. Li Jia-tai, Institute of Clinical Pharmacology, Beijing Medical University, Beijing, People's Republic of China.
Clinical Infectious Diseases 1997; 24:498-505
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2403 — 0031$02.00
Similar synergism is evident in the activity of this combination
against anaerobes [5-7].
We conducted the present clinical trial to evaluate sulbactam/
cefoperazone vs. the third-generation cephalosporin cefotaxime
in terms of efficacy and safety in hospitalized patients with
moderate-to-severe bacterial infections caused predominantly
by 0-lactamase-producing strains. This cooperative study was
performed from May 1993 to April 1994 at four sites in the
People's Republic of China: the Institute of Clinical Pharmacology, Beijing Medical University, and Beijing Hospital,
Beijing; Tian Jin Medical University, Tian Jin; and Da Lian
Medical University, Da Lian.
Patients and Methods
Study design. This randomized, open-label, parallel-group,
controlled, multicenter trial was designed to compare sulbactam/cefoperazone with cefotaxime in terms of efficacy and
safety for treating hospitalized patients with moderate-to-severe
bacterial infections. Before randomization, patients were stratified according to the site of infection (e.g., upper or lower
respiratory tract, urinary tract, or skin and soft tissue) so as to
ensure equal distribution of patients in the active treatment
(sulbactam/cefoperazone) and control (cefotaxime) groups.
Diagnostic criteria were stipulated in advance. The study design
stipulated that at least 80% of patients had to have positive
pretreatment bacterial cultures and that at least 50%-66% of
the isolated pathogens had to be /3-lactamase positive.
Patients. Hospitalized male and female patients between
the ages of 14 and 65 years were eligible for inclusion in the
CID 1997;24 (March)
Sulbactam/Cefoperazone vs. Cefotaxime 499
Table 1. Scores for the severity of infection in hospitalized patients who received sulbactam/cefoperazone or cefotaxime.
Type of infection, clinical variable
Respiratory infection*
Mental status
Normal
Moderately disoriented
Severely disoriented
Chills
Gastrointestinal symptoms
Fever
Temperature, ---38°C
Temperature, >38°C
Elevated WBC count
Lymph node tenderness
Pharyngalgia
Congestion of pharynx or tonsil
Peritonsillar pyoid secreta
Aphagia
Cough
Cough with yellow sputum
Thoracalgia
Dyspnea
Pulmonary percussion dullness
Pulmonary rale (dry/moist)
Radiographic findings Caurse lung markings
Pulmonary infiltration
Urinary tract infections
Mental status
Normal
Moderately disoriented
Severely disoriented
Score
0
1
2
2
2
2
2
2
1
2
1
2
2
2
1
2
0
Type of infection, clinical variable
Chills
Fever
Temperature, -.._.38°C
Temperature, >38°C
Elevated WBC count
Urination (frequent, precipitant, or painful)
Aching back
Lumbago
Urethral pyoid secreta
Tenderness of lower abdomen
Pain on percussion of kidney area
Urinary protein (+ ++ +)
Urinalysis
Presence of WBCs
Presence of WBCs and RBCs
Surgical infection
Elevated WBC count
Lymph node tenderness
Fever
Focal flushing, swelling, warmth, and pain
Secreta
Size of wound
<5 X 5 cm
>5 X 5 cm
Depth of wound
Epidermis
Dermis
Subcutaneous
Score
2
1
2
2
11
1
2
2
2
2
2
2
2
2
2
2
2
3
1
2
* Severity scores were as follows: mild,
moderate, 7-10; severe,
I. Severity scores were as follows: mild, -.7; moderate, 8-11; severe,
For each symptom that was present.
Severity scores were as follows: mild, 3-6; moderate, 7-11, severe,
study if their clinical signs and symptoms as well as their
laboratory test results were in accordance with diagnostic criteria for moderate-to-severe bacterial infections and if they had
not received effective antimicrobial treatment within 48 hours
of study enrollment. The scoring for assessment of moderateto-severe infections of the respiratory tract or urinary tract and
of surgical infections is shown in table 1.
Patients were excluded from the study if they had a history
of hypersensitivity to penicillins or cephalosporins; other significant allergies; severe cardiac, hepatic, renal, or hematopoietic system abnormalities; or terminal cancer. Patients were
also excluded if they had previously received treatment with
either sulbactam/cefoperazone or cefotaxime; had received any
other study drug within 4 weeks of study enrollment; or had
severe or potentially lethal infections requiring more potent
antibiotic treatment. Pregnant or lactating women also were
excluded, as were any patients who might die of any condition
within 48 hours of enrollment.
A patient who began randomized treatment could be withdrawn from the study if (1) a bacterial culture was negative
after the patient had received a 72-hour course of antimicrobial
therapy; (2) the isolated pathogen was resistant to both study
drugs; (3) the patient had a hypersensitivity reaction or other
severe adverse reaction to treatment that precluded the evaluation of efficacy; (4) the patient's symptoms worsened or there
was no significant improvement in the patient's condition after
72 hours of therapy; and/or (5) the patient had received any
additional antibiotic therapy during the trial.
Drugs. Sulbactam/cefoperazone (1:1 ratio) was given at a
dosage of 2-4 g/d in equally divided doses every 12 hours by
30-minute intravenous drip. Cefotaxime was given at a dosage
of 6-12 g/d in equally divided doses every 6-8 hours by 30minute intravenous drip. Each agent was prepared in 1-g doses
that were dissolved in 50-100 mL of normal saline or 5%
glucose solution.
Evaluation criteria. The efficacy and safety of the study
drugs were evaluated on the basis of changes in maximum
body temperature, clinical signs and symptoms, and (when
applicable) findings on chest radiographs and other objective
methods. Clinical laboratory tests (e.g., urinalysis, hematology,
500
CID 1997;24 (March)
Li et al.
and tests of hepatic and renal function) were performed at
baseline, on days 3 and 4 during therapy, at the end of treatment, and on day 7 after treatment was completed. All clinical
findings, including any changes in laboratory test results, were
classified as definitely drug related, possibly drug related, possibly non—drug related, definitely non—drug related, or unevaluable.
Pathogens were isolated, cultured, and identified at baseline,
during therapy, at the end of therapy, and 5 to 7 days after
therapy was discontinued. However, for patients with urinary
tract infections, including gonorrhea, urine was cultured at
baseline; 24, 48, and 72 hours after the start of therapy; at the
end of therapy; and 5-7 days after therapy was discontinued.
Disk susceptibility tests were performed on pretreatment isolates with use of sulbactam/cefoperazone, cefoperazone, cefotaxime, amoxicillin/clavulanic acid, and ticarcillin/clavulanic
acid. The nitrocefin procedure was used to identify 0-lactamase —producing strains.
Bacteriologic effectiveness at the end of therapy was graded
as follows: "eradication" (all pathogens were eradicated),
"partial eradication" (one of the original pathogens was eradicated), "persistence" (none of the original pathogens was eradicated), "eradication with colonization" (a new pathogen was
isolated at the end of therapy, but the patient did not have any
associated signs and symptoms), and "superinfection" (a new
pathogen was isolated, and there were associated signs and
symptoms). The overall bacterial clearance rate for each treatment group was defined as the proportion of the total number
of isolates present before therapy that were eradicated at the
end of therapy.
Overall efficacy was graded on the basis of a combination
of clinical observations (e.g., changes in signs and symptoms
of infection), bacteriologic response, and changes in laboratory
test results and was rated as "cure," "marked improvement,"
"improvement," or "failure." A grade of cure required resolution of all signs and symptoms of infection, eradication of the
pathogens, and normal laboratory test results. Marked improvement was graded as improvement in relation to any three of the
above four criteria, whereas a grade of improvement required
improvement in relation to any two of the four criteria. Failure
was defined as persistence or worsening of clinical signs and
symptoms after 72 hours of treatment. The overall efficacy rate
was defined as the proportion of patients in each treatment
group who were considered to be cured or whose conditions
had markedly improved.
Statistical methods. The matched-pairs t-test was used for the
analysis of quantitative data, and the x 2 test was used for the
analysis of qualitative data. Fisher's exact test was used to calculate P values, the percentage of total clinical isolates that were
susceptible to the treatment, the bacterial clearance rate, and the
rate at which enzyme-producing bacteria were recovered.
Results
Patient characteristics. A total of 235 patients were enrolled at four centers, 28 (11.9%) of whom were withdrawn
Table 2. Demographic and clinical characteristics of hospitalized
patients who received sulbactam/cefoperazone or cefotaxime for
moderate-to-severe bacterial infections.
Variable
Mean age (y) ± SD
Mean weight (kg) ± SD
No. (%) with indicated site of infection
Respiratory tract
Urinary tract
Skin, soft tissue, other
No. (%) with moderate-to-severe cases
Mean duration (d) of treatment ± SD
Mean total dose (g) given ± SD
No. (%) of patients with fever before
treatment
Mean duration (d) of fever ± SD
No. (%) of patients with an elevated
WBC count before treatment
Mean duration (d) of elevated WBC
count ± SD
Sulbactam/
cefoperazone
(n = 103)
Cefotaxime
(n = 104)
48± 15
62± 10
64-99
64±99
44 (43)
37 (36)
22 (21)
93 (90)
10 ± 2.8
39 -± 17
51 (49)
33 (32)
20 (19)
94 (90)
9.8 ± 2.9
39 -± 13
78 (76)
4.2 ± 2.5
75 (72)
4.4 ± 2.8
52 (50)
53 (51)
6.6 -± 3.1
3.1
6.2±3.1
NOTE. P > .05 for the comparison of data between the two groups.
from the study before beginning treatment. Of these 28 patients,
25 were withdrawn because of negative bacterial cultures, and
three were withdrawn because their isolates were resistant to
the two study drugs. No patients were withdrawn because of
persistence or worsening of signs and symptoms or the occurrence of adverse reactions within 72 hours of initiation of treatment.
The demographic and clinical characteristics of the 207 patients who completed the study and were included in the efficacy and safety evaluations are shown in table 2. One hundredthree patients were treated with sulbactam/cefoperazone, and
104 were treated with cefotaxime. Ninety-six (46%) of the 207
patients had respiratory infections (predominantly pneumonias), 70 (34%) had urinary tract infections (primarily pyelonephritis), and 42 (20%) had skin and/or soft-tissue infections or
other bacterial infections. There were no significant differences
between treatment groups with respect to demographic or other
baseline characteristics.
Efficacy. A total of 76 (74%) of the 103 patients treated
with sulbactam/cefoperazone were cured (i.e., all signs and
symptoms resolved, the pathogens were eradicated, and laboratory test results normalized), whereas 69 (66%) of the 104
patients treated with cefotaxime were cured (P = .243) (table
3). The overall efficacy rate (i.e., cure plus marked improvement) for the sulbactam/cefoperazone group was 95%, and that
for the cefotaxime group was 90%; there were no statistically
significant differences between the groups (P = .186).
The overall efficacy rates, by type of infection, were as
follows: sulbactam/cefoperazone and cefotaxime were 93% and
88%, respectively, for respiratory infections (P = NS); 100%
501
Sulbactam/Cefoperazone vs. Cefotaxime CID 1997;24 (March)
Table 3. Clinical efficacy of sulbactam/cefoperazone vs. cefotaxime for the treatment of moderate-to-severe bacterial infections in hospitalized
patients.
Cefotaxime*t (n = 104)
Sulbactam/cefoperazone* t (n = 103)
Site, type of infection
Respiratory tract
Unilateral or bilateral
pneumonia
Chronic bronchitis
(acute attack)
Acute bronchitis
Bronchiectasis, concurrent
infection
Acute tonsillitis
Acute nasal sinusitis
Pyothorax
Total
Urinary tract
Acute pyelonephritis
Chronic pyelonephritis
(acute attack)
Acute cystitis
Gonococcal urethritis
Acute prostatitis
Kidney stone, concurrent
urinary infection
Total
Skin, soft tissue, other sites
Wound infection
Furuncle, carbuncle, or
abscess
Tinea pedis, secondary
infection
Infection complicating
other skin diseases
Erysipelas
Mastadenitis
Pelvic inflammation
Celiac infection
Intracranial infection
Septicemia
Cholecystitis
Total
No. of
cases
Cure
Marked
improvement
Improvement
No. of
cases
Cure
Marked
improvement
Improvement
34
23
8
3
33
18
10
5
6
1
3
1
3
10
4
6
2
3
2
1
1
2
2
2
51
28
17
6
18
12
4
2
4
8
1
2
3
7
1
1
1
1
33
24
6
1
4
3
1
1
3
2
4
3
2
1
1
1
2
1
1
1
1
2
1
20
1
2
1
17
1
1
1
1
44
28
13
23
19
4
2
10
2
10
1
1
1
37
32
4
3
5
3
4
4
3
2
3
1
1
3
1
5
1
1
1
3
1
1
1
2
1
22
2
1
1
16
1
4
2
2
1
* Seventy-six (74%) of 103 patients in the sulbactam/cefoperazone group were cured vs. 69 (66%) of 104 in the cefotaxime group (P = .243).
t The overall efficacy rates (cure plus marked improvement) for the two groups were 98 (95%) of 103 patients in the sulbactam/cefoperazone group and 94
(90%) of 104 in the cefotaxime group (P = .186); there were no treatment failures in either group.
and 91%, respectively, for urinary and reproductive tract infections (P = .061); and 91% and 95%, respectively, for skin and
soft-tissue infections (P = NS).
One hundred seventy-eight pathogens were isolated from the
207 patients before treatment was started (table 4). The overall
rate of positivity was 86%, which exceeded the protocolstipulated rate of Of the 178 strains isolated (most
commonly from sputum), 85 were recovered from patients in
the sulbactam/cefoperazone group, and 93 were recovered from
patients in the cefotaxime group (table 4). As might be expected
for hospitalized patients with moderate-to-severe infections,
the pathogens most commonly isolated from the patients in
this study were Escherichia coli (49 [28%] of 178 isolates),
Klebsiella species (22 [12%]), S. aureus (22 [12%]), and Pseudomonas species (21 [12%]).
One hundred seventy-six of the 178 isolates were tested for
susceptibility; none was resistant to sulbactam/cefoperazone or
cefotaxime, while 12 (7%) were resistant to cefoperazone
alone, 98 (56%) were resistant to amoxicillin/clavulanic acid,
and 17 (10%) were resistant to ticarcillin/clavulanic acid (table
CID 1997; 24 (March)
Li et al.
502
Table 4. Identification and sources of pretreatment bacterial isolates recovered from hospitalized patients who received sulbactam/cefoperazone
or cefotaxime.
Cefotaxime
Sulbactam/cefoperazone
Sputum
Pus
Blood
Urine
Swab
Total
Sputum
Pus
Blood
Urine
Swab
Total
Escherichia coli
Klebsiella species
Enterobacter cloacae
Enterobacter aerogenes
0
7
3
2
0
0
1
0
Other Enterobacteriaceae
Citrobacter species
Serratia species
Proteus species
Acinetobacter species
Pseudomonas species
0
1
0
0
4
7
1
0
0
0
0
4
1
0
1
0
0
0
0
0
0
0
Haemophilus influenzae
Hafnia alvei
0
1
Other glucose nonfermenters
Enterobacter agglomerans
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus hemolyticus
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
20
9
4
1
1
1
0
2
5
14
0
1
2
2
12
5
3
0
13
6
3
1
1
2
2
3
4
3
0
0
1
0
1
3
4
0
0
0
0
0
0
0
2
2
0
0
0
0
6
1
0
0
0
0
15
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
23
0
1
0
0
1
0
1
0
1
0
0
0
0
3
0
0
0
0
1
30
0
0
0
0
0
0
0
0
1
0
0
0
0
0
1
0
0
0
0
0
2
29
13
7
3
1
2
2
3
6
7
3
0
0
1
10
2
3
0
0
1
93
Pathogen
Group D enterococci
Neisseria gonorrhoeae
Total
0
0
2
0
0
1
1
1
7
0
0
0
2
3
2
0
0
0
17
2
0
0
0
0
0
2
1
3
0
0
0
0
4
1
0
1
0
0
0
0
1
0
1
0
35
0
0
17
0
0
2
1
0
31
0
0
0
2
0
85
0
0
44
0
Table 5. Susceptibility testing results for isolates recovered from hospitalized patients with bacterial infections.
No. of isolates with indicated susceptibility
Sulbactam/
cefoperazone
Ticarcillin/
clavulanic acid
Amoxicillin/
clavulanic acid
Cefotaxime
Cefoperazone
Pathogen
S
I
R
S
I
R
S
I
R
S
I
R
S
I
R
Pseudomonas species
Klebsiella species
Escherichia coli
Enterobacter cloacae
Acinetobacter species
Serratia species
Enterobacter aerogenes
20
21
42
1
1
6
0
1
0
1
0
1
0
0
0
0
0
0
0
3
0
2
0
16
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
19
16
35
10
5
2
1
2
1
4
0
2
3
3
1
5
15
5
0
1
130
1
5
11
1
3
0
1
0
2
1
1
0
0
0
0
0
6
0
2
0
34
1
1
2
0
3
0
2
0
0
0
0
0
0
0
0
1
1
1
0
0
12
9
14
40
8
9
1
1
2
1
4
0
2
3
3
1
4
13
6
0
0
121
12
8
8
3
2
1
3
0
2
1
1
0
0
0
0
2
9
0
2
1
55
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
7
12
0
6
1
1
0
0
1
0
0
0
3
1
4
14
6
2
1
61
3
3
5
2
0
0
1
0
1
0
0
1
0
0
0
1
0
0
0
0
17
16
12
31
9
5
1
2
2
2
4
1
1
3
0
0
1
8
0
0
0
98
19
17
33
5
8
1
2
2
1
2
0
2
3
3
1
4
18
6
1
1
129
1
4
12
1
3
0
1
0
0
3
0
0
0
0
0
0
3
0
1
0
29
1
1
3
5
0
1
1
0
2
0
1
0
0
0
0
2
0
0
0
0
17
Other Enterobacteriaceae
Citrobacter species
Proteus species
11
10
2
3
2
2
5
Hafnia alvei
1
Other glucose nonfermenters
2
3
3
Enterobacter agglomerans
Haemophilus influenzae
Neisseria gonorrhoeae
Staphylococcus epidermidis
Staphylococcus aureus
Streptococcus pneumoniae
Group D enterococci
Streptococcus hemolyticus
Total
No. of highly susceptible
pathogens over total
no. of pathogens (%)
1
6
19
6
0
1
160
160/176 (91)
130/176 (74)
121/176 (69)
61/176 (35)
129/175 (74)
NOTE. For the comparison between the sulbactam/cefoperazone and cefoperazone groups, P = .002; for the comparison between the sulbactam/cefoperazone
and cefotaxime groups, P = .001. S = highly susceptible; I = intermediately susceptible; R = resistant.
CID 1997;24 (March)
Sulbactam/Cefoperazone vs. Cefotaxime 503
Table 6. Identification of enzyme-producing bacterial strains recovered from hospitalized patients with moderate-to-severe infections who
received sulbactam/cefoperazone or cefotaxime.
Sulbactam/cefoperazone*
Pathogen
Escherichia coli
Pseudomonas species
Klebsiella species
Citrobacter species
Enterobacter cloacae
Acinetobacter species
Enterobacter aerogenes
Enterobacter agglomerans
Other Enterobacteriaceae
Proteus species
Serratia species
Haemophilus influenzae
Hafnia alvei
Cefotaximet
Total no. of
strains of
indicated
pathogen
No. positive for
fi-lactamase
No. negative for
/3-lactamase
20
14
9
17
11
7
3
3
2
1
1
4
5
4
4
1
1
2
2
2
2
12
4
3
8
2
Total no. of
strains of
indicated
pathogen
2
1
Other glucose nonfermenters
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus hemolyticus
Group D enterococci
2
4
2
3
28
8
13
2
6
6
3
No. positive for
fi-lactamase
No. negative for
fi-lactamase
22
5
10
2
5
4
3
6
3
3
3
1
3
1
10
2
3
1
2
2
1
3
1
7
3
2
3
2
NOTE. P = .601 when the sulbactam/cefoperazone group was compared with the cefotaxime group.
* Of a total of 84 strains, 60 (71%) were positive for /3-lactamase.
t Of a total of 90 strains, 61 (68%) were positive for /3-lactamase.
5). Of the susceptible isolates, 160 (91%) were highly susceptible to sulbactam/cefoperazone, whereas only 121 (69%) were
highly susceptible to cefotaxime. This difference between
groups was statistically significant (P = .001). The difference
between the rates of susceptibility to sulbactam/cefoperazone
and to cefoperazone alone (130 [74%] of 176) was also statistically significant (P = .002).
As noted earlier, the nitrocefin procedure was used to identify 0-lactamase—producing strains among 174 clinical isolates
(table 6). Sixty (71%) of 84 strains recovered from patients in
the sulbactam/cefoperazone group and 61 (68%) of 90 strains
recovered from patients in the cefotaxime group produced 0lactamase; these numbers exceeded the study design requirement that two-thirds of the isolates be /3-lactamase positive.
The difference between the treatment groups was not statistically significant (P = .601)
The overall bacterial clearance rates for the sulbactam/cefoperazone group and the cefotaxime group at the end of treatment were 85% and 81%, respectively; no statistically significant difference was observed between groups (table 7).
Safety. Both drug treatments were well tolerated. Overall,
17 (8.2%) of 207 patients had generally mild, drug-related
adverse reactions; 8 (7.8%) of 103 patients in the sulbactam/
cefoperazone group had reactions, and 9 (8.7%) of 104 in the
cefotaxime group had reactions (P = .831) (table 8). Treatment
was not discontinued because of side effects or death for any
patient in either group. One case of rash was reported in the
sulbactam/cefoperazone group, whereas one case of nausea and
three cases of phlebitis were reported in the cefotaxime group.
Laboratory abnormalities were reported for seven patients in
the sulbactam/cefoperazone group and five patients in the cefotaxime group.
Discussion
The results of this randomized, controlled, multicenter trial
indicate that 1 or 2 grams of sulbactam/cefoperazone (1:1 ratio),
dissolved in 50-100 mL of normal saline or in 5% glucose
solution and given every 12 hours by a 30-minute intravenous
drip, is effective for treating infections of the respiratory tract,
urinary tract, and skin and/or soft tissues as well as other moderate-to-severe bacterial infections in hospitalized patients.
There were no statistically significant differences between sulbactam/cefoperazone and the control agent, cefotaxime, with
regard to clinical efficacy or bacterial clearance.
These findings are consistent with the results reported in
other clinical trials [8-11]. For example, the results of a
multicenter clinical trial conducted by Hara et al. [8] and published in 1985 showed no significant difference between sulbac-
504
CID 1997;24 (March)
Li et al.
Table 7. Bacterial clearance rates among hospitalized patients who received sulbactam/cefoperazone or cefotaxime.
Cefotaximet
Sulbactam/cefoperazone*
Pathogen
Escherichia coli*
Klebsiella species
Enterobacter cloacae
Enterobacter aerogenes
Other Enterobacteriaceae
Citrobacter species
Serratia species
Proteus species
Acinetobacter species
Pseudomonas species
Haemophilus influenzae
Hafnia alvei
Other glucose nonfermenters
Enterobacter agglomerans
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus hemolyticus
Group D enterococci
Neisseria gonorrhoeae
Total no.
of strains
No. (%)
eradicated
20
9
4
1
1
1
0
2
5
14
0
1
2
2
12
5
3
1
2
0
17 (85)
7 (78)
4 (100)
1 (100)
1 (100)
1 (100)
0
2 (100)
4 (80)
9 (64)
0
1 (100)
2 (100)
1 (50)
11 (92)
5 (100)
3 (100)
1 (100)
2 (100)
0
No.
persisting
No. causing
superinfections
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Total no.
of strains
No. (%)
eradicated
No.
persisting
No. causing
superinfections
29
13
7
3
1
2
2
3
6
7
3
0
0
1
10
2
3
0
0
1
24 (83)
8 (62)
7 (100)
1 (33)
1 (100)
2 (100)
1 (50)
3(100)
5 (83)
4 (57)
3 (100)
0
0
0
10 (100)
2 (100)
3 (100)
0
0
1 (100)
2
4
0
1
0
0
1
0
1
3
0
0
0
0
0
0
0
0
0
0
2
1
0
1
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
NOTE. P = .467 when the sulbactam/cefoperazone group was compared with the cefotaxime group.
* Of 85 strains isolated, 72 (85%) were eradicated.
t Of 93 strains isolated, 75 (81%) were eradicated.
Among patients from whom E. coli was isolated, there was one case of reinfection in the sulbactam/cefoperazone group and one case of relapse in the
cefotaxime group.
Table 8. Adverse reactions among hospitalized patients with bacterial infections who received sulbactam/cefoperazone or cefotaxime.
Reaction
Clinical adverse reaction
Rash
Nausea
Phlebitis
Laboratory abnormalities
Elevated alanine
aminotransferase level
Elevated alanine
aminotransferase and
alkaline phosphatase
levels
Elevated alanine
aminotransferase and
aspartate aminotransferase
levels
No. who received
sulbactam/
cefoperazone
with indicated
reaction
No. who received
cefotaxime with
indicated reaction
0
0
0
5
1
3
4
0
1
NOTE. The rate of adverse reactions was 7.8% in the sulbactam/cefoperazone group and 8.7% in the cefotaxime group (P = .831).
tam/cefoperazone and cefotaxime with regard to efficacy and
safety in 56 patients with respiratory tract infections.
Although most of the patients in the present study had lower
respiratory tract infections, only 3 (1.7%) of the 178 isolated
pathogens were Haemophilus influenzae, and only 6 (3.4%)
were Streptococcus pneumoniae. While this finding may appear
paradoxical, our study population consisted primarily of patients with moderate-to-severe nosocomial infections that were
most frequently caused by gram-negative rods, —70% of which
produced 41-lactamase.
The results of disk susceptibility tests in our trial showed that
none of the strains were resistant to sulbactam/cefoperazone or
cefotaxime, whereas 12 (6.9%) of 176 strains were resistant to
cefoperazone alone. Moreover, 91% of the strains were highly
susceptible to sulbactam/cefoperazone, as compared with 74%
that were highly susceptible to cefoperazone alone (P = .002).
These observations are consistent with the observations from
other studies [1, 2, 4, 12] and suggest that the addition of the
enzyme inhibitor sulbactam enhances the antibacterial activity
of cefoperazone against resistant, 0-lactamase —producing
strains. The potential clinical benefit of the combination of
sulbactam/cefoperazone is supported by the results of another
clinical trial [9] in which sulbactam/cefoperazone was found
to be significantly more effective than cefoperazone alone in
the treatment of urinary tract infections.
CID 1997; 24 (March)
Sulbactam/Cefoperazone vs. Cefotaxime
In our trial, both regimens were well tolerated. Clinical adverse reactions and laboratory abnormalities occurred in only
17 (8.2%) of the 207 patients. The adverse reaction rates for
sulbactam/cefoperazone and cefotaxime were both low (7.8%
and 8.7%, respectively) and did not differ significantly in incidence.
The results of this study demonstrate that the combination
of sulbactam/cefoperazone is effective and safe when used to
treat hospitalized patients with a variety of moderate-to-severe
bacterial infections, the majority of which are caused by
0-lactamase—producing organisms.
Acknowledgments
The authors thank Pfizer Pharmaceuticals, Ltd. (Da Lian, China)
for providing sulbactam/cefoperazone and Hoechst, Inc. for providing cefotaxime.
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