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Antimicrobial Agents and Chemotherapy, August 2000, p. 2028-2033, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Monotherapy with a Broad-Spectrum Beta-Lactam Is as Effective
as Its Combination with an Aminoglycoside in Treatment of Severe
Generalized Peritonitis: a Multicenter Randomized Controlled
Trial
H.
Dupont,1,*
C.
Carbon,2 and
J.
Carlet3,
for The Severe Generalized
Peritonitis Study Group
Departments of Surgical
ICU1 and Internal
Medicine,2 University Hospital Bichat, and
Department of Medical and Surgical ICU, Saint Joseph
Hospital,3 Paris, France
Received 13 January 2000/Returned for modification 28 February
2000/Accepted 1 May 2000
 |
ABSTRACT |
In a randomized trial conducted in 35 centers, we compared the
clinical efficacy and safety of piperacillin plus tazobactam (TAZ)
alone (monotherapy [MT]) versus those of TAZ combined with amikacin
(AMK) (combined therapy [CT]) for the treatment of severe generalized
peritonitis (SGP). Primary analysis consisted of blind assessment by an
independent committee of the failure rate 30 days after the end of
treatment in the modified intent-to-treat (ITT) analysis (mITT)
population. Of the 241 patients with suspected SGP randomized into the
study, 227 were eligible for ITT analysis, including 204 (99 in the MT
group and 105 in the CT group) with confirmed SGP (mITT population). A
total of 159 patients were eligible for per-protocol (PP) analysis. The
clinical failure rates were equivalent in the mITT and PP populations
(MT versus CT): 56 versus 52%, (odds ratio [OR] 0.87, 90%
confidence interval [CI] = 0.6 to 1.27) for mITT and 49 versus 49%
(OR = 1.03, 90% CI = 0.67 to 1.59) for PP analysis.
Mortality rates (ITT population, 19%; PP population, 21%) and overall
adverse event rates (ITT population, 55%; PP population, 54%) were
also similar. Six patients (three in MT group and three in the CT
group) developed acute renal failure. In conclusion, the addition of
AMK to TAZ does not seem to be necessary for the treatment of SGP, even
after adjustment for the simplified acute physiology score (SAPS II) and type of SGP.
| |
INTRODUCTION |
Severe generalized peritonitis (SGP)
is frequently encountered, and the rate of mortality associated with
SGP ranges from 10 to 60% (17, 22, 24). Initial antibiotic
therapy, in addition to surgery, must be started early and must cover
all pathogens that can cause intra-abdominal infections (gram-negative
bacilli, anaerobes, and enterococci) (5, 17). The recent
increase in the rate of multiple-antibiotic resistance among
gram-negative bacilli such as Escherichia coli justifies
empiric initial treatment with a broad-spectrum antibiotic. The
treatment can subsequently be adapted according to antibiotic
susceptibility test results. The addition of an aminoglycoside to the
treatment regimen has many theoretical advantages: (i) a broader
spectrum of activity, (ii) increased synergy, (iii) increased
bactericidal effect, and (iv) prevention of emergence of resistant
strains (26). However, no study that has supported the use
of aminoglycosides for the treatment of SGP has been published in the
literature (14, 15). The aim of this study was to compare,
by means of an equivalence trial, the effect of a broad-spectrum
beta-lactam antibiotic (piperacillin-tazobactam) alone or in
combination with an aminoglycoside (amikacin) in the treatment of SGP.
(This work was presented in part at the 38th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998 [H. Dupont, C. Carbon, J. Carlet, H. Schweich, and
the SGP Study, Program 38th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. MN-48, p. 602, 1998].)
| |
MATERIALS AND METHODS |
Participants.
This study was conducted in 35 centers in
France. The trial protocol was reviewed and approved by an independent
ethics committee in accordance with the ethical principles of the
Declaration of Helsinki. Informed consent was obtained from each
patient (or from his or her legal representative) before enrollment in
the study. Eligible patients were men or nonpregnant women, ages 18 years or older, with a clinical diagnosis of complicated
intra-abdominal infection according to previously published criteria
(30). Complicated intra-abdominal infection was defined by
the presence of severe sepsis for patients with community-acquired
infections and at least systemic inflammatory response syndrome (SIRS)
for patients with postoperative or nosocomial infections. SIRS and
severe sepsis were defined as reported previously (3). SIRS
was defined by two or more of the following conditions: (i)
temperature, >38°C or <36°C; (ii) heart rate, >90 beats/min;
(iii) respiratory rate of >20 breaths/min or partial arterial
CO2 pressure of <32 mmHg, and (iv) leukocyte count,
>12,000/mm3 or <4,000/mm3. Severe sepsis was
defined by at least one of the following criteria: (i) hypotension with
systolic blood pressure of <90 mmHg; (ii) oliguria (output, 
30
ml/h); (iii) acute alteration in mental status; (iv) coagulation
abnormalities, such as a prothrombin time of <50% or a platelet count
of <100,000/mm3; (v) partial arterial O2
pressure of <60 mm Hg or partial arterial O2
pressure/fractional inhibitory O2 pressure of <250; and
(vi) blood lactate concentration, >2 mmol/liter.
Noninclusion criteria for this study included allergy to beta-lactam
antibiotics or aminoglycosides, MacCabe and Jackson score of C
(19) or simplified acute physiology score (SAPS II) of >45
(18), septic shock (3), neutropenia (leukocyte
count, <1,000/mm3), pregnancy, nongeneralized peritonitis,
and effective antimicrobial treatment given during the 30 days prior to
inclusion. Patients eligible for intent-to-treat (ITT) analysis were
those randomized after they gave their signed informed consent. The
modified ITT (mITT) analysis population was the ITT population that
presented with a surgically proven complicated intra-abdominal
infection and corresponded to the main analysis population. The
per-protocol (PP) population included all patients in the mITT
population with no major protocol violation (exclusion criterion).
Methods.
This prospective, randomized, open-label trial was
conducted to compare monotherapy (MT; piperacillin plus tazobactam)
versus combined therapy (CT; piperacillin plus tazobactam and amikacin) for the treatment of SGP. Computer-generated randomization of the
subjects into blocks of four subjects each was used, and each center
was allocated one block of the MT treatment group and one block of the
CT treatment group to ensure a stratified distribution.
No standardization of the postsurgerical approaches were planned for
the protocol. Briefly, all wounds were left closed. Mesh
was not
usually placed on the wound, but mesh placement was left
to the
discretion of the surgeon. Abdomens were not irrigated
in this
study.
Piperacillin plus tazobactam was administered intravenously at a dose
of 4 g four times daily to both groups. Amikacin was
administered
intravenously at a dose of 7.5 mg/kg of body weight
twice daily (30-min
infusion) to the CT group. The dose of amikacin
could be reduced
according to renal function and antibiotic concentrations
in blood. The
duration of treatment was at least 2 days and up
to 14
days.
Successful treatment was defined by the following criteria: (i)
normalization of body temperature, (ii) normalization of abdominal
and
systemic signs, (iii) no clinical or laboratory signs of persistent
residual abscess, and (iv) no need for surgery or new antimicrobial
therapy during the observation period until day 30 after the end
of
treatment. Clinical failure was defined by at least one of
the
following criteria: (i) no response or deterioration during
treatment,
(ii) death from any cause, (iii) any reoperation for
abdominal surgery,
even for wound infections, (iv) any change
in antimicrobial treatment
except for the use of antifungal agents,
(vi) any serious adverse event
related to antibiotic treatment,
and (vii) the desire of the patient to
stop participation in the
trial.
Efficacy and failure rates were assessed at the end of treatment and
after the 30-day posttreatment follow-up period by an
evaluation
committee blinded to the antibiotic regimen received.
The primary
endpoint was the failure rate for the mITT population
at day 30 posttreatment. Secondary endpoints were the time to
failure for the
mITT population, the duration of treatment for
cured patients in the
mITT population, and the adverse event rate
for the ITT
population.
At least two sets of aerobic and anaerobic samples for blood culture
were obtained by perioperative venipuncture. Peritoneal
fluid samples
were obtained intraoperatively. Antibiotic susceptibility
was assessed
by the disk diffusion method, and breakpoints were
defined by the
Antibiotic Susceptibility Testing Committee of
the Société
Française de Microbiologie (
10).
Analysis.
Sample size estimation for the primary endpoint
was based on a two-sample test of proportions with 
equal to 10%
and a power probability of 71%. The study was powered with a 15%
tolerance around equivalence for the percent failure rate for the MT
group. We calculated that at least 100 patients would be required in each treatment group to achieve this power, assuming a 35% failure rate for patients in the MT group. A total of 241 patients were recruited to compensate for possible protocol violations. The primary
analysis was based on mITT analysis of all randomized patients. The
failure rate was analyzed by using a logistic regression model adjusted
for SAPS II (a cutoff value of 30, which corresponded to the median
SAPS II for the population, was used) and type of infection
(community-acquired or postoperative infection). The odds ratio for the
CT group versus the MT group was estimated. The 90% confidence
interval (CI) of the odds ratio was calculated and was then compared
with the equivalence interval (0.54 to 1.82) calculated before the
beginning of the study. Equivalence was demonstrated if the 90% CI was
totally included within the equivalence interval (2, 11).
Time to failure and duration of treatment for cured patients were
analyzed by using a Cox model adjusted for both SAPS II
and type of
infection (community-acquired or postoperative infection).
The hazard
ratios for the CT group versus the MT group were estimated.
The 90%
CIs of the hazard ratios were calculated and then compared
with the
equivalence interval (0.66 to 1.53). Equivalence was
demonstrated when
the 90% CI was totally included within the equivalence
interval.
Demographic and baseline features and adverse event rates were compared
by the chi
2-square test or the
t test. Failure
rates were analyzed by the
log-rank test, and Kaplan-Meier estimates
were plotted over the
30-day posttreatment observation
period.
No interim analysis was planned by the
protocol.
| |
RESULTS |
Patients.
Patients were recruited between March 1994 and July
1997: 241 patients were randomized into the study, with 227 patients
eligible for ITT analysis (Fig. 1).
Fourteen patients were excluded after they withdrew their consent. In
accordance with French law, data for none of these randomized patients
were included in the study or in the database. Twenty-three patients
were excluded from ITT analysis because of the absence of
intra-abdominal infection (12 in the MT group and 11 in the CT group).
Forty-five major protocol violations were reported during the study (18 in the MT group and 27 in the CT group): previous effective
antimicrobial treatment during the 30 days prior to inclusion for 17 patients, SAPS II score of >45 for 14 patients, MacCabe and Jackson
score C for 9 patients, uncontrolled septic shock for 4 patients,
duration of treatment of less than 2 days for 3 patients, neutropenia
(leukocyte count, <1,000/mm3) for 1 patient, and
miscellaneous violations for 6 patients.
Demographic and baseline features were similar for the MT and CT groups
of the mITT population (Table
1). No
difference in
baseline laboratory data was observed between the two
groups (data
not shown). The main etiologies of generalized peritonitis
are
presented in Table
2.
The pathogens isolated from peritoneal fluid are summarized in Table
3. No difference in frequency was
observed between the
two groups. Eighty-eight percent of the pathogens
isolated from
peritoneal fluid were sensitive to tazobactam and 71%
were sensitive
to amikacin, with no difference between the two groups.
When only
gram-negative bacilli are considered, nine organisms from the
MT group and eight organisms from the CT group were intermediate
or
resistant to piperacillin-tazobactam and yet sensitive to amikacin.
Otherwise, only one gram-negative bacillus from the MT group and
five
gram-negative bacilli from the CT group were resistant to
amikacin and
yet sensitive to piperacillin-tazobactam. Seventeen
percent of patients
had concomitant positive blood cultures: 14
in the MT group and 21 in
the CT group (
P = 0.26). The main pathogens
isolated
from blood cultures were
E. coli for 35.6% of the patients,
Bacteroides spp. for 23.7% of the patients, and
Enterococcus spp.
for 8.5% of the patients.
The mean daily dose of tazobactam was 12.9 g ± 2.5 for the MT
group, whereas it was 12.8 g ± 2.7 for the CT group. The mean
duration of tazobactam treatment was 8.2 ± 4.5 days for the MT
group and 8.6 ± 3.7 days for the CT group. The mean daily dose
of
amikacin was 13.2 ± 3.3 mg/kg for the CT group, and the mean
duration of amikacin treatment was 6 ± 2.6 days. Dopamine was
used more frequently for the CT group than for the MT group (53
versus
39%;
P = 0.04).
Endpoints.
Primary and secondary endpoints in the main
population analysis (the mITT population) are summarized in Table
4. For the mITT population, assessment by
the evaluation committee demonstrated equivalence between the MT and CT
groups for the failure rate after the 30-day posttreatment follow-up
period. Equivalence was also demonstrated for the time to failure and
the duration of treatment for cured patients. No differences in failure
rates were observed between the two groups (Fig.
2). Failure essentially occurred during
the treatment period (Table 5), with no
difference between the groups (62% for the MT group versus 53% for
the CT group). Failures corresponded to secondary modification of the antibiotic therapy due to complications (53%) and unexpected surgery due to complications (28%), with no difference between the groups. Failure was potentially related to the antibiotic resistance of the
pathogens in 11.5% of patients in the MT group and 10% of patients in
the CT group for community-acquired infections and in 31% of failures
in the MT group versus 32% of failures in the CT group for
postoperative and nosocomial infections.
Equivalence between the two regimens was also demonstrated by the
evaluation committee for the PP population in terms of the
failure rate
after the 30-day posttreatment follow-up period and
for time to failure
and duration of treatment for cured patients
(Table
6).
Adverse events.
All adverse events are reported in Table
7. No difference was observed between the
two regimens, especially for the frequency of renal failure in the CT
group. The overall mortality rate was 19.8%. Serious adverse events
due to treatment were allergic manifestations due to beta-lactam
antibiotics: skin rash, thrombocytopenia, and liver enzyme
abnormalities.
| |
DISCUSSION |
To our knowledge, this is the first study to demonstrate the
strict equivalence of failure rates between treatments with a broad-spectrum beta-lactam antibiotic alone and in combination with an
aminoglycoside in a population with SGP. Time to failure was also the
same between the two regimens, and the duration of treatment was
equivalent for cured patients. Aminoglycosides were not responsible for
a higher incidence of renal failure.
The number of patients excluded after randomization following failure
to give informed consent was due to the emergency procedure used to
obtain informed consent with secondary assessment. However, these
exclusions were well balanced between the two groups. As described
above, mITT analysis was the main analysis according to the general
guidelines for the evaluation of new anti-infective drugs for the
treatment of intra-abdominal infections (30). Only patients
with a proven intra-abdominal infection were evaluated in this study in
order to obtain a homogeneous population. The inclusion of patients
with uncomplicated appendicitis (1, 12, 24) or patients with
a low Apache II score (12, 31) is the main criticism of most
studies that evaluate antibiotic regimens for peritonitis. All patients
included in this study presented with SGP, with a mean SAPS II of 30, SIRS, and severe sepsis according to previously described criteria for
patients with complicated intra-abdominal infections (3).
This trial was also adjusted by logistic regression for SAPS II and
type of infection (community-acquired or postoperative infection).
It has been suggested that inappropriate initial antibiotic treatment
for intra-abdominal infections increases the incidence of postoperative
infectious events (12, 24), the reoperation rate
(24), and the rate of mortality from community-acquired and
postoperative peritonitis (22, 24), even when antimicrobial therapy is secondarily adapted (12, 24). It therefore
appeared to be of major interest to evaluate the impact of the addition of an aminoglycoside to a broad-spectrum beta-lactam antibiotic on the
overall outcomes of these severe infections.
The failure rate observed in this study (50%) was higher than that
reported in previous recent studies: 30% by Cometta et al.
(9) when death was included, 18% by Barie et al.
(1), and 20% for Brismar et al. (4). The rate of
mortality from postoperative peritonitis may be as high as 50%
(22), and patients with postoperative peritonitis
represented 43% of our study population. Our very strict definitions
of failure may largely explain these results.
The value of an aminoglycoside in combination with a broad-spectrum
beta-lactam antibiotic for intra-abdominal infections is still
controversial. Broad-spectrum beta-lactam antibiotics have been
successfully used alone for the treatment of intra-abdominal infections: imipenem-cilastatin (1, 7, 9, 29), meropenem (7), piperacillin-tazobactam (4), and cefepime
(1). Most studies included patients with low Apache II
scores and achieved treatment success rates as high as 90%; in most
cases the diagnosis was appendicitis (17, 27). Only the
study by Cometta et al. (9) compared monotherapy with
combined therapy with the same beta-lactam antibiotic
(imipenem-cilastatin) and netilmicin (9). Their results, for
which were for patients with peritonitis but also patients with other
infections such as pneumonia and bacteremia, showed no difference in
success rates between the MT group and the CT group. The addition
of netilmicin increased the rate of nephrotoxicity and did not prevent
the emergence of imipenem-resistant Pseudomonas aeruginosa.
No significant difference was observed in the peritonitis subgroup, but
no failure due to antibiotic resistance was observed.
No studies that have compared MT versus CT during severe peritonitis
are available in the literature. The equivalence design of our study
allowed us to conclude that the addition of amikacin to piperacillin
plus tazobactam was not justified for the treatment of SGP. In the
1980s the use of an aminoglycoside was justified by the lack of
broad-spectrum beta-lactam antibiotics (29). Recent reviews
of the literature demonstrate that there is no clear evidence in
support of the use of aminoglycosides for the treatment of peritonitis
for the following more or less theoretical reasons (8, 14,
17). Aminoglycosides have a good diffusion into the peritoneal
cavity (20), but they may be ineffective because their
activity is reduced by the local intra-abdominal conditions of acidosis
and hypoxia and the presence of drug-binding purulent debris (21,
28). They have a marked postantibiotic effect on gram-negative
bacilli, but no study has been specifically devoted to intra-abdominal
infections (16). Combination therapy with an aminoglycoside
has been used to increase the spectrum of antibiotic treatment and to
exert a synergistic action with beta-lactam antibiotics against most
bacteria (26). Prevention of the emergence of resistant
strains of bacteria such as P. aeruginosa has been
suggested, but none of the published studies demonstrated such an
effect (9, 14, 15). Aminoglycoside treatment has also been
shown to be associated with an increased incidence of nephrotoxicity
(from 4 to 50%) (9, 14, 15).
Another problem is the rates of bacteremia observed concomitantly with
the peritonitis. Patients with bacteremia represent a subgroup with
potentially severe illness who could obtain greater benefit from
treatment with an aminoglycoside. This has been demonstrated only for
neutropenic patients with bacteremia (6). It should also be
noted that in our study the percentage of patients with bacteremia was
equivalent between the two regimens. Another important point in this
study is the small number of patients from whom P. aeruginosa was isolated. Isolation of P. aeruginosa
depends on the etiology of the intra-abdominal infection: for patients with community-acquired infections, it varies from 3% (16)
to 5% in our study, and for patients with postoperative infections, it
varies from 11.5% in our study to 21% (22, 25, 29).
Patients with P. aeruginosa infections might obtain greater
benefit from aminoglycosides, but this has not been formally
demonstrated. The emergence of enterococci may complicate treatment
options during severe intra-abdominal infections. The use of an
aminoglycoside, which has been validated for the treatment of
enterococcal endocarditis (13, 32), has never been
validated for the treatment of clinically severe enterococcal
intra-abdominal infections. Moreover, the addition of gentamicin in an
experimental model of rat polymicrobial peritonitis did not increase
the enterococcal killing rate (23). However, the number of
enterococci isolated in this study may be too low to demonstrate such
an effect.
In conclusion, our results do not support the addition of an
aminoglycoside such as amikacin to piperacillin plus tazobactam for the
treatment of SGP. The value of combination therapy with aminoglycosides
remains to be specifically validated for Pseudomonas spp.
and enterococci during complicated intra-abdominal infections. However,
in this large study that included patients with both community-acquired
and postoperative or nosocomial SGP, neither of these microorganisms
raised any major problems.
| |
APPENDIX |
The members of the Severe Generalized Peritonitis Study Group are
(all cities are in France) B. Allaouchiche (Lyon), P. Boissel (Vand
uvre les Nancy), A. Brachet (Châlon sur Saône), Y. Chapuis (Paris), P. Clot (Paris), F. Dazza (Paris), J. M. Desmonts
(Paris), J. Domergue (Montpellier), P. Erny (Bordeaux), J. P. Faller (Belfort), J. P. Favre (Dijon), J. B. Flament (Reims),
F. Fraisse (Saint-Denis), F. Gayral (Le Kremlin Bicêtre), B. Berbaud (Bourg en Bresse), M. Gonzales (Lisieux), J. L. Gouzi
(Toulouse), D. Guelon (Clemond-Ferrand), J. M. Hay (Colombes), B. Henry (Amiens), M. Huguier (Paris), P. Kieffer (Altkirch), M. J. Laisne (Paris), B. Launois (Rennes), J. C. Le Neel (Nantes), A. Lepape (Lyon), P. Macchi (Nice), M. Malafosse (Paris), B. Millat
(Montpellier), J. L. Ricome (Saint-Germain-en-Laye), J. Ronceray
(Angers), H. Rosay (Mont Saint-Martin), D. Tardy (Bry sur Marne), P. Teniere (Rouen), and M. Vankemmel (Lille).
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Wyeth-Lederle
Laboratories France.
Statistical analysis was performed by Effi-Stat, Paris, France.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Département d'Anesthésie Réanimation
Chirurgicale, CHU Bichat Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. Phone: (33) 140258118. Fax: (33) 140258869. E-mail:
aphp{at}hdupont.claranet.fr.
The members of the Severe Generalized Peritonitis Study Group are
listed in the Appendix.
| |
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Antimicrobial Agents and Chemotherapy, August 2000, p. 2028-2033, Vol. 44, No. 8
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
