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Background. The addition of an aminoglycoside to a b-lactam therapy regimen has been suggested to have
a beneficial effect in delaying or preventing the development of antimicrobial resistance. We studied the effect of
aminoglycoside/b-lactam combination therapy versus b-lactam monotherapy on the emergence of resistance.
Methods. We performed a meta-analysis of randomized, controlled trials (RCTs) that compared aminoglycoside/b-lactam combination therapy with b-lactam monotherapy and that reported data regarding the emergence
of resistance (primary outcome) and/or development of superinfection, treatment failure, treatment failure attributable to emergence of resistance, treatment failure attributable to superinfection, all-cause mortality during
treatment, and mortality due to infection. Data for this meta-analysis were identified from the PubMed database,
Current Contents database, Cochrane central register of controlled trials, and references in relevant articles.
Results. A total of 8 RCTs were included in the analysis. b-Lactam monotherapy was not associated with a
greater emergence of resistance than was the aminoglycoside/b-lactam combination (odds ratio [OR], 0.90; 95%
confidence interval [CI], 0.561.47). Actually, b-lactam monotherapy was associated with fewer superinfections
(OR, 0.62; 95% CI, 0.420.93) and fewer treatment failures (OR, 0.62; 95% CI, 0.381.01). Rates of treatment
failure attributable to emergence of resistance (OR, 3.09; 95% CI, 0.7512.82), treatment failure attributable to
superinfection (OR, 0.60; 95% CI, 0.331.10), all-cause mortality during treatment (OR, 0.70; 95% CI, 0.401.25),
and mortality due to infection (OR, 0.74; 95% CI, 0.461.21) did not differ significantly between the 2 regimens.
Conclusions. Compared with b-lactam monotherapy, the aminoglycoside/b-lactam combination was not
associated with a beneficial effect on the development of antimicrobial resistance among initially antimicrobialsusceptible isolates.
Combination antimicrobial therapy has been tried for
the management of a variety of infectious diseases, primarily because drugs with different mechanisms of action may act synergistically (i.e., a 14-fold decrease in
the MIC of each drug when tested together against a
pathogen in vitro). Combination therapy may also allow the use of smaller doses of each of the combined
drugs. The initial successful example of clinical use of
1
Alfa Institute of Biomedical Sciences (AIBS) and 2Department of Medicine, Henry Dunant Hospital, Athens, and 3Department of Medicine,
University of Crete, School of Medicine, Iraklion, Greece; and 4Department of Medicine, Tufts University School of Medicine, Boston,
Massachusetts
Table 1. Reported data on the emergence of antimicrobial resistance and superinfection from the randomized, controlled trials
included in the analysis
Treatment regimen
Mono arm
Combo arm
Duration of
treatment
Time of
clinical
evaluation
Year
Patient population
Setting
[61]
1995
Czid, 2 g q12h
No limit
At end of treatment
and 14 days AT
[62]
1994
No limit
[74]
1993
ICUs in a US hospital
No limit
[67]
1992
12 German and 5
Austrian hospitals
172 h
At end of treatment
[12]
1989
US hospital
Mez, 4 g q6h
15 days and
At end of treatment
and after 2
months
15 days and
14 days and
No limit; treatment
stopped after 3
afebrile days
[21]
[30]
[33]
1987
1985
1983
Canadian hospitals
US hospital
Canadian hospital
Czid, 2 g q8h
Czid, 2 g q8h
!30 days
At end of treatment
!21 days
!16 days
NOTE. Amp, ampicillin; AT, after treatment; Carb, carboxypenicillin; Cfaz, cefazolin; Cil, cilastatin; combo arm, aminoglycoside/b-lactam combination therapy
arm; Cper, cefoperazone; Ctax, cefotaxime; Ctri, ceftriaxone; Czid, ceftazidime; Gm, gentamicin; ICU, intensive care unit; Imi, imipenem; LRTI, lower respiratory
tract infection; Mez, mezlocillin; mono arm, b-lactam monotherapy arm; ND, data not reported; Net, netilmicin; Pip, piperacillin; Tic, ticarcillin; Tm, tobramycin.
a
b
c
d
Study
No. of
clinically
evaluable
patients
No. of
microbiologically
evaluable
patients
Predominant organisms
isolated before treatment
(% of patients)
No. of
patients with
reisolation of
initial pathogen /
no. of patients
No. of
patients with
emergence of
resistant isolates /
no. of patients
No. of
patients with
super-infections /
no. of patients
Frequency of
follow-up cultures
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
3045 days AT
261
230
197
188
Pseudomonas aeruginosa,
Klebsiella species, Escherichia coli, Acinetobacter
species, Staphylococcus
aureus
24-day intervals
during treatment
and 14 days AT
ND
ND
12/197
14/188
14/306
20/274
None
142
138
98
101
Not specified
ND
ND
6/98
9/101
8/142
11/138
None
39
70
39
70
At day 5, day 7, or if
symptoms
persisted
6/39
14/70
5/39
13/70
11/39
34/70
None
144
124
94
68
7/144
6/124
1/94
1/68
ND
ND
Up to 3 years
24
22
24
22
Days 1, 3, and 5
and 48 h, 2
weeks, and 8
weeks AT
4/24
9/22
0/24
0/22
0/24
3/22
30 Days AT
52
58
37
38
Not specified
12/57c
14/64c
2/37
0/38
3/52
5/58
None
21
19
21
19
Staphylococcus species, P.
aeruginosa, Streptococcus
pneumoniae, K. pneumoniae
Not specified
ND
ND
0/21
0/19
3/21
0/19
2 Weeks or up
to hospital
discharge
26
24
21
17
8/21
5/17
6/21
2/17
5/26
4/24
mediate or to resistant, or from initially intermediate to resistant). Secondary outcomes of the analysis were development
of superinfection (i.e., isolation of a pathogen thought to be
responsible for an infection that was of a different species from
the initially isolated pathogen), treatment failure (no response
to treatment, no clinical improvement, clinical deterioration,
or death from infection), treatment failure attributable to emergence of resistance, treatment failure attributable to superinfection, all-cause mortality during treatment, and mortality due
to infection.
Data analysis and statistical methods. Statistical analyses
were performed using Meta-analyst software (Joseph Lau; Tufts
University School of Medicine, Boston, MA). The heterogeneity
between studies was assessed by using a x2 test; a P value of
!.10 was used to note statistical significance in the analysis of
heterogeneity [7]. Publication bias was assessed by the funnel
plot method using Eggers test [8]. Pooled ORs and 95% CIs
for all primary and secondary outcomes were calculated by use
of both the Mantel-Haenszel fixed-effects and the DerSimonian-Laird random-effects models [9, 10]. For all analyses,
results from the fixed-effects model are presented only when
Duration of
follow-up
Table 2. Reported data on mortality and treatment failure from the randomized, controlled trials included
in the analysis.
All-cause
mortality
Mortality
attributable
to infection
Treatment
failure
Treatment
failure due
to emergence
of resistance
Treatment
failure due to
superinfections
Study
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
Mono
arm
Combo
arm
[61]
[62]
20/261
ND
21/230
ND
8/261
18/142
14/230
13/138
34/261
29/142
51/230
19/138
4/261
ND
0/230
ND
ND
3/142
ND
5/138
[74]
[67]
[12]
ND
2/144
ND
ND
5/124
ND
2/39
0/144
0/24
7/70
0/124
3/22
17/39
11/144
4/24
48/70
12/124
13/22
ND
1/144
0/24
ND
0/124
0/22
11/39
ND
0/24
34/70
ND
3/22
[21]
[30]
[33]
ND
1/21
ND
ND
2/19
ND
ND
ND
2/26
ND
ND
3/24
5/52
3/21
6/26
8/58
4/19
6/24
ND
0/21
1/26
ND
0/19
0/24
ND
3/21
2/26
ND
0/19
0/24
NOTE. Data are no. of patients with finding or result/no. of clinically evaluable patients. Combo arm, aminoglycoside/b-lactam
combination therapy arm; mono arm, b-lactam monotherapy arm; ND, data not reported.
Figure 1. Emergence of antimicrobial resistance in randomized controlled trials comparing b-lactam monotherapy with aminoglycoside/b;-lactam
combination therapy. The size of each square denotes the proportion of information given by each trial. Vertical line, no difference point in emergence
of antimicrobial resistance between the 2 regimens; horizontal lines, 95% CIs; squares, ORs; diamond, pooled OR for all studies. GA Study Group,
German and Austrian Imipenem/Cilastin Study Group.
Figure 2. Development of superinfections in randomized, controlled trials comparing b-lactam monotherapy with aminoglycoside/b-lactam combination therapy. The size of each square denotes the proportion of information given by each trial. Vertical line, no difference point in development
of superinfections between the 2 regimens; horizontal lines, 95% CIs; squares, ORs; diamond, pooled OR for all studies.
Aminoglycoside/b-Lactam Resistance Emergence CID 2005:41 (15 July) 153
and outcomes related to the emergence of antimicrobial resistance have not been consistent. For example, 3 studies that
examined the emergence of antimicrobial resistance in initially
antimicrobial-susceptible Enterobacter clinical isolates reported
different results. Chow et al. [76] (in a prospective, noninterventional study) and Lee et al. [77] (in a retrospective study)
reported that emergence of resistance to the administered blactam therapy did not occur less frequently among patients
receiving aminoglycoside/b-lactam combination therapy than
among patients receiving b-lactam monotherapy. On the other
hand, in a retrospective study, Kaye et al. [78] reported a lower
rate of emergence of antimicrobial resistance with the use of
aminoglycoside/b-lactam combination therapy, compared with
b-lactam monotherapy, although this finding was not statistically significant. Furthermore, 2 studies that examined the
emergence of resistance (among other outcomes) in patients
with pneumonia who received combination antimicrobial therapy or monotherapy also reported conflicting results. In a large
retrospective study, Kosmidis et al. [79] reported that a lower
rate of emergence of resistance was noted among patients with
154 CID 2005:41 (15 July) Bliziotis et al.
Figure 3. Treatment failure due to any reason (A), due to emergence of resistance (B), or due to superinfections (C) in randomized, controlled trials
comparing b-lactam monotherapy with aminoglycoside/b-lactam combination therapy. The size of each square denotes the proportion of information
given by each trial. Vertical line, no difference point in development of superinfections between the 2 regimens; horizontal lines, 95% CIs; squares,
ORs; diamond, pooled OR for all studies. GA Study Group, German and Austrian Imipenem/Cilastin Study Group.
the results from these studies; aminoglycoside/b-lactam combination therapy is associated with more clinical failures, but
no difference in mortality rates has been found between the 2
regimens.
Our study has several limitations that should be taken into
account when interpreting the results. The most important limitation is that most of the RCTs tested a different b-lactam in
the compared treatment arms. Therefore, one may claim that
development of resistance was influenced by the different blactams in the compared study arms, thus confounding the
effect of aminoglycosides on this outcome, as well as other
outcomes. However, the results of the analysis of data on the
emergence of resistance from 2 studies in which the same blactam was administered in both study groups showed similar
results with those of the full set of the studied RCTs.
Another limitation of our study is that the available RCTs
comparing b-lactam monotherapy versus aminoglycoside/b-
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Acknowledgments
Potential conflicts of interest. All authors: no conflicts.
21.
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