Journal of Antimicrobial Chemotherapy (2006) 57, 639–647

doi:10.1093/jac/dkl044
Advance Access publication 24 February 2006

The role of aminoglycosides in combination with a b-lactam for

the treatment of bacterial endocarditis: a meta-analysis of
comparative trials

Matthew E. Falagas1,2*, Dimitrios K. Matthaiou1 and Ioannis A. Bliziotis1

1
Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece;
2
Department of Medicine, Tufts University School of Medicine, Boston, MA, USA

Received 2 November 2005; returned 15 December 2005; revised 27 January 2006; accepted 30 January 2006

Downloaded from http://jac.oxfordjournals.org/ by guest on July 22, 2016

Background: The addition of an aminoglycoside to a b-lactam for the treatment of patients with infective
endocarditis has been supported by data from laboratory and animal studies.
Purpose: We sought to review the evidence from the available comparative clinical trials regarding the
role of aminoglycosides in combination with a b-lactam for the treatment of bacterial endocarditis caused
by Gram-positive cocci.
Data sources: The studies for our meta-analysis were retrieved from searches of the PubMed and Cochrane
Central Register of Controlled Trials databases, as well as from the references cited in relevant articles.
No limits were set regarding the language and date of publication of the studies.
Study selection: Included studies were prospective studies that provided comparative data regarding
the effectiveness of the treatment and/or mortality in patients receiving monotherapy with a b-lactam or
b-lactam/aminoglycoside combination therapy.
Data extraction: Two independent reviewers performed the literature search, study selection and extrac-
tion of data from relevant studies.
Data synthesis: No clinical trial comparing b-lactam monotherapy with b-lactam/aminoglycoside combina-
tion therapy for the treatment of enterococcal endocarditis was found. We performed a meta-analysis of five
available comparative trials [four randomized controlled trials (RCTs) and one comparative prospective
trial], which included 261 patients with bacterial endocarditis in native valves due to Staphylococcus aureus
(four studies) or streptococci of the viridans group (one study). There was no statistically significant
difference between b-lactam monotherapy and b-lactam/aminoglycoside combination therapy regarding
mortality [odds ratio (OR) = 0.59, 95% confidence interval (95% CI) = 0.21–1.66], treatment success
(OR = 1.25, 95% CI = 0.49–3.05), treatment success without surgery (OR = 1.66, 95% CI = 0.64–4.30) or
relapse of endocarditis (OR = 0.79, 95% CI = 0.15–4.29). Nephrotoxicity was less common in the b-lactam
monotherapy arm than in the b-lactam/aminoglycoside combination therapy arm (OR = 0.38, 95%
CI = 0.16–0.88, P = 0.024). No difference between the two treatment arms was found in subanalyses of
the four studies that included only patients with staphylococcal infections in terms of mortality (OR = 0.69,
95% CI = 0.26–1.86, fixed effects model), treatment success (OR = 1.27, 95% CI = 0.47–3.43, fixed effects
model) or relapse (OR = 0.76, 95% CI = 0.12–4.92, fixed effects model).
Limitations: The relatively small number of available comparative trials was the major limitation of this
meta-analysis.
Conclusions: The limited evidence from the available prospective comparative studies does not offer
support for the addition of an aminoglycoside to b-lactam treatment of patients with endocarditis caused
by Gram-positive cocci. A large multicentre RCT is necessary to reach a definitive conclusion on this issue.

Keywords: gentamicin, oxacillin, nafcillin, Staphylococcus, Streptococcus

.............................................................................................................................................................................................................................................................................................................................................................................................................................

*Correspondence author. Tel: +30-694-611-0000; Fax: +30-210-683-9605; E-mail: m.falagas@aibs.gr

.............................................................................................................................................................................................................................................................................................................................................................................................................................

639

The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org
 Systematic review
Introduction
b-Lactams are considered an important part of the medical treat-
ment of patients with bacterial endocarditis since Gram-positive
cocci are the aetiological agents in the vast majority of cases
with this infection. Combination therapy of b-lactam with an
aminoglycoside has been tested both in vitro and in clinical
studies, but results, especially from clinical studies, are often
contradictory. The combination of an aminoglycoside with a
b-lactam has been shown to exhibit partial or full synergy against
a variety of isolates in some laboratory studies.1–4 However, the
potential increase in the effectiveness of an antimicrobial regi-
men after the addition of an aminoglycoside should be weighed
against the increased toxicity that may be conferred by the
aminoglycoside. Consequently, the need for the addition of an
aminoglycoside in the treatment of patients with certain types
of bacterial endocarditis has been questioned.5,6 In addition, the
continuous changes of the susceptibilities of pathogens to
antibiotics make the decision regarding the appropriate medical
therapy for bacterial endocarditis more complex.7–9
We sought to further examine the role of aminoglycosides
as combination therapy with a b-lactam in the treatment of
patients with bacterial endocarditis. Although there have been
few reviews in the literature about this issue, they are mostly
narrative.10–12 Thus, we systematically reviewed the available
clinical data from studies that compared b-lactam monotherapy
with the b-lactam/aminoglycoside combination therapy in terms
of effectiveness and toxicity.
Methods
Data sources
Two independent reviewers performed the literature search, study
selection and extraction of data (D. K. M. and I. A. B.). Any
disagreement between the two reviewers was resolved by consensus
in meetings that involved all authors. The studies for our meta-
analysis were retrieved from searches of the PubMed and
Cochrane Central Register of Controlled Trials databases and
from references cited in relevant articles. Search terms included
‘endocarditis’, ‘randomized control trial’, ‘clinical trial’, ‘lactam’,
‘aminoglycoside’, ‘monotherapy’ and ‘combination therapy’.
Study selection
The relevant studies identified were further evaluated. A study was
considered eligible if (i) it was a randomized controlled trial (RCT)
or a prospective comparative trial; (ii) it compared b-lactam mono-
therapy with the b-lactam/aminoglycoside combination therapy for
the treatment of bacterial endocarditis caused by Gram-positive
cocci; and (iii) it examined the effectiveness of the treatment and/
or mortality. Studies examining different b-lactams in each treatment
arm were not excluded from the analysis. No limits were set regard-
ing the language and date of publication of the studies. Endocarditis
was defined by at least two positive blood cultures not attributable to
other sources of infection, together with other clinical, imaging or
laboratory findings considered by the authors of the trials as being
consistent with endocarditis. In addition, Duke criteria were
considered sufficient to define endocarditis.13,14
Data extraction
Various characteristics and outcomes of interest were extracted from
each of the studies included. A quality review of each RCT included
640
in our analysis was performed using the Jadad score, which examines
whether there is randomization, blinding and information on with-
drawals in the study and evaluates the appropriateness of random-
ization and blinding, if present.15,16 One point was awarded for the
presence of each of the first three criteria, whereas the last two
criteria could take the values of –1 (inappropriate), 0 (no data)
and +1 (appropriate). Thus, the maximum score for a study was
5, and a score of more than 2 points denoted a good quality
RCT. The scoring system was the same for both independent review-
ers and it was calculated independently by each of them.
Outcomes
The primary outcome of the analysis was the effectiveness of each
administered regimen. Treatment was considered successful when
the clinical findings of endocarditis had resolved and there was
no further evidence (any laboratory or imaging finding) of active
endocarditis after the completion of therapy and during the follow-up
of the patients. Secondary outcomes were treatment success without
the need for surgical repair of the affected valve(s), mortality, neph-
rotoxicity (defined as a twofold rise in the serum creatinine level
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compared with the baseline value of creatinine during the start of
treatment) and occurrence of relapse (defined as the isolation of the
same pathogen from blood specimens during the follow-up).
Statistical analyses
Statistical analyses were performed using the Meta-analyst software
(Joseph Lau, Tufts University School of Medicine, Boston, MA).
We presented results from the fixed effects models when there
was no heterogeneity between the studies analysed (P value >
0.1). Otherwise, we presented results from the random effects mod-
els. Pooled odds ratios (OR) and confidence intervals (CI) for all the
outcomes were calculated using the Mantel–Haenszel fixed effects
and the DerSimonian–Laird random effects models. A finding was
considered statistically significant if there was a P value < 0.05 in the
analysis of the outcomes. Secondary analyses were performed for
different subsets of studies based on the study design, the patient
population and the isolated pathogen.
Results
Selected studies
In Figure 1 we present a flow diagram showing the consecutive
steps that were followed in order to identify the appropriate
studies. A total of 29 studies were identified as most
relevant,17–50 19 of which were excluded because, although
they were prospective, they were non-comparative studies, and
10 were excluded because, although they were comparative pro-
spective studies, they compared other treatment regimens (e.g. b-
lactam monotherapy against glycopeptide monotherapy or short
against long duration b-lactam/aminoglycoside combination ther-
apy). Thus, we included in our meta-analysis four evaluable
RCTs and one prospective comparative clinical study that
were performed in patients with bacterial endocarditis comparing
b-lactam monotherapy with b-lactam/aminoglycoside combina-
tion therapy.46–50
The main characteristics of these studies are presented in
Table 1. In four studies (three RCTs and the one prospective
study), the pathogen causing endocarditis was Staphylococcus
aureus,46–49 and the pathogens were streptococci of the viridans
group in the remaining RCT (2 of the 51 patients of this study had
 Systematic review

1983 potentially relevant studies included in our analysis (Table 1). In each of the studies
articles identified and screened included, the same b-lactam was administered in both treatment
for retrieval arms, although this was not mandated by our inclusion criteria.
Owing to the fact that four of five studies presented data for
253 articles were excluded as
irrelevant to our subject
S. aureus infections, oxacillin, cloxacillin and nafcillin were the
b-lactams tested in three of these studies, whereas various peni-
1730 studies including any kind
cillinase-resistant b-lactams were used in the fourth study. Ceftri-
of pathogen of infectious axone was the b-lactam used for the treatment of patients in the
endocarditis were further RCT that examined streptococcal infections. The aminoglycoside
evaluated used in all studies was gentamicin, mainly at a daily dosage of
3 mg/kg body weight. Other aminoglycosides (although not spe-
114 studies were excluded because cifically reported) were also used in some patients in the com-
they referred to pathogens other than parative study by Rajashekaraiah et al.48 Both the intramuscular
Gram-positive cocci
and the intravenous route of administration of aminoglycosides
were used in the selected trials. In one study the aminoglycoside
1616 potentially appropriate
studies regarding endocarditis
was administered once daily,50 and in three studies multiple times
caused by Gram-positive cocci daily,46,47,49 whereas in one study the dosage scheme was not
of various methodologies, clearly stated.48
including RCTs

1405 studies were excluded because Treatment success

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211 studies of several different
prophylactic or therapeutic
regimens
34 potentially evaluable
prospective studies evaluating
β-lactams or aminoglycosides
for the treatment of endocarditis
caused by Gram-positive cocci17–50
4 RCTs plus 1 prospective
comparative study were
included in our
meta-analysis46–50
they were case reports, reviews,
guidelines, epidemiological,
retrospective, experimental or
laboratory studies
177 studies were excluded because
they examined prophylactic
regimens or therapeutic regimens
other than the ones evaluated in our
meta-analysis
29 studies were excluded
• 19 studies were excluded
because they were non-
comparative17–19,21,22,24,27–30,
32,33,36,39,40,42–45
• 10 studies were comparative;
however, they compared
different regimens than the
ones of interest for our meta-
analysis20,23,25,26,31,34,35,37,38,41
Data regarding treatment success are summarized in Table 2.
Overall treatment success was reported in each treatment arm
in all RCTs included in our paper, whereas no clear definition
for treatment success was provided in the prospective comparat-
ive study; thus, this study was excluded from the analysis of
treatment success. There was no statistically significant differ-
ence between the two arms (OR = 1.25, 95% CI = 0.49–3.05,
fixed effects model) (Figure 2). Also, no difference regarding this
outcome was found between the monotherapy and combination
therapy in a sensitivity analysis of three RCTs that examined
staphylococcal infections (OR = 1.27, 95% CI = 0.47–3.43,
fixed effects model) or in a subset of patients who were intra-
venous drug addicts (OR = 1.07, 95% CI = 0.29–3.94, fixed
effects model).
Treatment success without surgery
Treatment success without the need for surgical repair of the
affected valves was reported in three RCTs (Table 2). No
statistically significant difference was found between the two
treatment arms (OR = 1.66, 95% CI = 0.64–4.30, fixed effects
model).
Mortality

Figure 1. Flow diagram of article review.

endocarditis due to Streptococcus bovis).50 As shown in Table 1,
the studies included patients with both left-sided and right-sided
native valve infective endocarditis. Quality analysis of the four
RCTs showed that the mean Jadad score of the studies was 2.5,
but two of them scored only 2 points. The prospective com-
parative study was not assessed in terms of quality, since this
specific score system is not appropriate for non-RCT studies.
Administration of drugs
A variety of b-lactam agents was used in the monotherapy and
consequently in the comparator combination therapy arm of the
Mortality was reported in all studies included in our meta-
analysis. The data regarding mortality are also summarized in
Table 2. There was no statistically significant difference regard-
ing mortality between the monotherapy and combination therapy
groups (OR = 0.59, 95% CI = 0.21–1.66, fixed effects model)
(Figure 3). Also, no difference in mortality between the treatment
arms compared was found in sensitivity analyses of mortality of
patients in the four RCTs, excluding the prospective comparative
study (OR = 0.40, 95% CI = 0.10–1.59, fixed effects model), and
in intravenous drug addicts (OR = 0.45, 95% CI = 0.12–1.64,
fixed effects model). Finally, no statistically significant differ-
ence was found in mortality between the compared treatment
arms when the four studies that examined patients with S. aureus
infections were analysed separately (OR = 0.69, 95% CI = 0.26–
1.86, fixed effects model).

641
 Table 1. Main characteristics of the trials analysed

Authors/year of
publication/ Quality Drugs tested Minimum
reference score Clinically follow up
number/study of the Patient Causative combination Criteria for ITT evaluable after end
design study population pathogen Type of BE monotherapy therapy BE diagnosis patients patients of therapy

Sexton et al./ 2 multicentre Streptococcus left-sided BE

ceftriaxone ceftriaxone Duke criteria13,14 67 51 3 months
1998/50/open study; the great viridans and 2 g qd iv 2 g qd iv
RCT majority of Streptococcus for 4 weeks plus
patients were bovis (in 4% gentamicin
non-IVDA of the patients) 3 mg/kg qd
(94%) for 2 weeks
Ribera et al./ 3 exclusively methicillin- exclusively cloxacillin cloxacillin definite: 2 positive blood 90 74 6 months
1996/49/open IVDA; in both susceptible right-sided 2 g q4h iv 2 g q4h iv cultures plus U/S evidence
RCT study arms Staphylococcus endocarditis for 14 days plus of tricuspid vegetation or
90% were aureus gentamicin direct evidence from
HIV-positive 1 mg/kg q8h histological and
with a mean iv for the bacteriological study of

642
CD4 count first 7 days vegetation
300–350 probable: 2 positive
blood culture
Systematic review

plus pulmonary emboli,

or new murmur, or U/S
evidence
possible: 2
positive blood cultures,
without other evident
source of infection, plus
fever, with or without
chest pain, dyspnoea,
cough or haemoptysis
Korzeniowski 3 both IVDA S. aureus primarily right- nafcillin 9– nafcillin 9– at least two positive 90 IVDA, 60 48 IVDA, 1 month
et al./1982/47/ and non-IVDA; sided BE in 12 g/day iv 12 g/day blood cultures in a non-IVDA 30 non-
open RCT at the time of IVDA and q4h or q6h, iv q4h or patient with clinical IVDA
presentation left-sided in for 6 weeks q6h, for presentation consistent
most IVDA non-IVDA 6 weeks plus with BE (fever, cardiac
suffered from gentamicin murmur, embolic
septic 1 mg/kg phenomena)
pulmonary iv or im q8h,
emboli for the first
2 weeks

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 Abrams et al./ 2 exclusively S. aureus 20 patients 12 g qd of 12 g qd of 3 or more positive 37 25 NR*
1979/46/open IVDA; the had right- penicillinase- penicillinase- blood cultures plus
RCT majority of sided resistant resistant penicillin radiographic
patients had involvement penicillin or or cephalosporin for evidence or
extracardiac alone, 2 cephalosporin 4 weeks plus auscultatory
septic emboli left-sided, for 4 weeks gentamicin 80 mg evidence of
in lungs, CNS and 3 had q8h for the first murmur or U/S
or joints both sides 2 weeks evidence of
affected vegetations
Rajashekaraiah NA both IVDA sensitive or right-sided BE IVDA (right-sided BE): IVDA (right-sided BE): IVDA: at least 50 33 NR
et al./1980/48/ and non-IVDA tolerant strains in IVDA oxacillin or nafcillin oxacillin or nafcillin 4/6 positive blood
prospective of S. aureus and left-sided 12 g qd for 4 to 12 g qd for 4 to cultures, taken
comparative (tolerance was in non-IVDA 6 weeks 6 weeks plus over at least a
study defined as Non-IVDA (left-sided gentamicin 2 h period plus
MBC/MIC ‡16 BE): penicillinase- 4.5 mg/kg/d for at X-ray with
when pathogen resistant penicillin least 7 days. septic pulmonary
was tested or cephalosporin Non-IVDA emboli not due
against for 4 to 6 weeks (left-sided BE): to peripheral
oxacillin, penicillinase- thrombophlebitis
nafcillin or resistant penicillin Non-IVDA: new
cefalotin) or cephalosporin left-sided murmur
plus an or left-sided
aminoglycoside valvular lesion
for at least 7 days with peripheral

643
or visceral embolic
phenomena but no
pulmonary emboli
Systematic review

BE, bacterial endocarditis; ITT, intention to treat; IVDA, intravenous drug abusers; NA, not applicable; non-IVDA, non-intravenous drug abusers; NR, not reported; qd, every day; q8h, every 8 h; q6h, every 6 h; q4h,
every 4 h; RCT, randomized controlled trial; iv, intravenous; im, intramuscular; U/S, ultrasound.

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 Systematic review

0/25 (0%)
1/36 (3%)

1/22 (4%)
0/19 (0%)
0/13 (0%)
Nephrotoxicity
Nephrotoxicity was reported for each treatment arm in three

Relapse
RCTs (Table 2). Nephrotoxicity occurred less often in the b-

NR
lactam monotherapy arm, compared with the b-lactam/

0/26 (0%)
0/38 (0%)

0/22 (0%)
1/11 (9%)
0/12 (0%)
aminoglycoside combination therapy, a result with statistical
significance (OR = 0.38, 95% CI = 0.16–0.88, P = 0.024,
fixed effects model).

Relapse

11/19 (58%)
5/36 (20%)

5/24 (21%)
2/25 (8%)

Four RCTs reported data regarding relapse of bacterial endocard-

Nephrotoxicity

itis after therapy (Table 2). Most of the episodes of relapse

reported in the included studies occurred a few days after the
NR
NR
completion of therapy. There was no statistically significant
b-lactam monotherapy versus b-lactam/aminoglycoside combination

difference regarding relapse between the b-lactam monotherapy

5/24 (21%)
0/26 (0%)
3/38 (8%)

1/11 (9%)

and the b-lactam/aminoglycoside combination therapy arms

(OR = 0.79, 95% CI = 0.15–4.29, fixed effects model). No dif-
ference in relapse was found in two sensitivity analyses, in the
subset of patients with staphylococcal infections (OR = 0.76, 95%
CI = 0.12–4.92, fixed effects model) and in the subset of addicts
6/19 (32%)

5/21 (24%)
0/25 (0%)
2/36 (6%)

0/22 (0%)

0/13 (0%)

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(OR = 0.43, 95% CI = 0.06–3.11, fixed effects model).
Mortality

Discussion
3/12 (25%)
0/26 (0%)
1/38 (3%)

1/22 (5%)
1/11 (9%)
0/12 (0%)

The purpose of our study was to compare the effectiveness

and several secondary outcomes between b-lactam monotherapy
and b-lactam/aminoglycoside combination therapy of
patients with bacterial endocarditis. The main finding of our
study is that the evidence available from the trials analysed
13/13 (100%)
15/25 (60%)

13/19 (68%)

does not show any special benefit for the addition of an

aminoglycoside to a b-lactam treatment of patients with bacterial
Treatment success

endocarditis. On the contrary, such an addition can lead to

without surgery

increased nephrotoxicity.
IVDA, intravenous drug addicts; non-IVDA, non-intravenous drug addicts; NR, not reported.

It is interesting that our literature search retrieved only five

NR

NR

NR

published comparative trials examining this clinically important

12/12 (100%)
21/26 (81%)

7/11 (64%)

question in patients with staphylococcal or streptococcal endo-

carditis. In addition, we could not find any trial that compared the
effectiveness and toxicity of the b-lactam monotherapy and the
Table 2. Primary and secondary outcomes of the trials analysed

b-lactam/aminoglycoside combination therapy for enterococcal

endocarditis. It should be noted that the addition of an aminoglyc-
oside to a b-lactam for the treatment of bacterial endocarditis
13/13 (100%)
24/25 (96%)
32/36 (89%)

13/14 (93%)
13/19 (68%)

was originally supported by in vitro, animal and some non-

comparative clinical studies.5,18,51–53 However, this practice
does not seem to be supported by the available prospective com-
success (cure)
Treatment

parative studies and RCTs, which represent the definitive way to

answer questions regarding the effectiveness and toxicity of
NR

various therapeutic regimens.

12/12 (100%)
25/26 (96%)
34/38 (90%)

14/15 (93%)
8/11 (73%)

The latest recommendations for the treatment of patients

with bacterial endocarditis, published by the American Heart
Association (AHA) in 2005, suggest that in the case of S. aureus
infections of native valves an optional addition of gentamicin to
oxacillin or nafcillin could be made for the first 3–5 days and
comment that benefits from such an addition have not been
Abrams et al./1979/46
publication/reference

Sexton et al./1998/50
Ribera et al./1996/49

established.54 On the other hand, in the case of S. bovis or

streptococcal infections of the viridans group, the addition of
et al./1982/47

et al./1980/48
Authors/year of

Rajashekaraiah
Korzeniowski

gentamicin to penicillin G or ceftriaxone is highly recommended

non-IVDA

by the AHA for the first 2 weeks of treatment. Our findings are in
IVDA

accordance with the suggestions of the AHA regarding S. aureus

number

bacterial endocarditis, but they cannot provide support for the

recommendations regarding the streptococcal infections because

644
 Systematic review
Study (Ref.)
Sexton 1998 (44)
Ribera 1996 (43)
Korzeniowski 1982 (41)
Abrams 1979 (40)
Combined
0.02 Favours combination 1.00 Favours monotherapy 58.65
Odds ratio (log scale)
Figure 2. Odds ratios of clinical cure (treatment success) between patients who
received b-lactam monotherapy and those who received b-lactam/aminoglyc-
oside combination therapy. Vertical line = ‘no difference’ point in treatment
success between the two regimens. Horizontal lines = 95% CI. Square = odds
ratio; the size of each square denotes the proportion of information given by each
trial. Diamond = pooled odds ratio for all studies.
Study (Ref.)
Sexton 1998 (44)
Ribera 1996 (43)
Rajasjekerai 1980 (42)
Korzeniowski 1982 (41)
Abrams 1979 (40)
Combined
0.02 Favours monotherapy 1.00 Favours combination 58.65
Odds ratio (log scale)
Figure 3. Odds ratios of all-cause mortality between patients who received
b-lactam monotherapy and those who received b-lactam/aminoglycoside com-
bination therapy. Vertical line = ‘no difference’ point in all-cause mortality
between the two regimens. Horizontal lines = 95% CI. Square = odds ratio;
the size of each square denotes the proportion of information given by each
trial. Diamond = pooled odds ratio for all studies.
of the lack of available evidence from clinical trials. The only
RCT reporting on streptococcal endocarditis included in our
analysis does not show any important benefit from the addition
of gentamicin. However, it should be noted that combination
therapy was found to be as effective as b-lactam monotherapy,
despite the fact that the drugs in the combination arm were
administered for a significantly shorter period.
There are several limitations of our study that should be taken
into consideration. First of all, one can claim that the number of
645
the studies and the number of patients that we included in our
analysis is relatively small to allow a safe conclusion to be drawn
regarding the effect of the therapies compared on the examined
outcomes. Second, the definitions for bacterial endocarditis used
in each study varied to some degree. This fact, in combination
with the overall scarcity of comparative prospective studies
examining the available treatment options for bacterial endocard-
itis, made us adopt an inclusive definition for bacterial endocard-
itis. Third, it should be mentioned that aminoglycoside serum
concentrations were measured systematically in only two of
the five studies included,47,50 a fact that may have influenced
both the recorded effectiveness and nephrotoxicity in the com-
bination therapy treatment arm. Fourth, we did not examine other
secondary outcomes such as time to defervescence and overall
toxicity of the compared regimen because not all studies reported
sufficient data to perform meaningful analyses.
Also, we included in our meta-analysis comparative trials that
were performed in different time periods and examined different
populations and b-lactams. However, we performed several
sensitivity analyses focusing on more homogeneous subsets of
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patients, such as intravenous drug addicts and patients with
bacterial endocarditis caused by S. aureus, in order to further
evaluate our main research question. In addition, it should be
noted that the inclusion of comparative trials with some differ-
ences in various characteristics such as study design, patient
population and setting is considered to be one of the strengths
of systematic reviews and meta-analyses, because it examines
the generalizability of a main clinical question.
Bacterial endocarditis is an infection that still causes consid-
erable morbidity and mortality worldwide. The choice of medical
treatment of patients with bacterial endocarditis, both regarding
the type of antibiotic used and its duration, is a difficult task
because several factors should be taken into account.54 These
include the heart valve affected, whether the valve is prosthetic
or native and the type of infecting organism, as well as the
immune status and the general health condition of the patient.
We believe that despite the limitations of the study, our meta-
analysis offers potentially useful information regarding the
management of bacterial endocarditis.
In conclusion, the meta-analysis of the available clinical trials
that compared b-lactam monotherapy with b-lactam/aminoglyc-
oside combination therapy for the treatment of bacterial endo-
carditis caused by Gram-positive cocci suggested that there was
no benefit in the effectiveness for the combination therapy. On
the contrary, there was a statistically significant increase in
renal toxicity when the b-lactam/aminoglycoside combination
therapy is used. It should be emphasized that the findings of
our study should be interpreted with caution owing to the relat-
ively small number of available prospective comparative studies
examining this issue. We believe that the results of our meta-
analysis underline the great need for a large, well-designed RCT
examining various aspects in the treatment of patients with
bacterial endocarditis.
Acknowledgements
We thank George J. Sermaides, MSc, for his help in the statistical
analysis of the data. Funding: none. Authors’ contributions: M. E. F.
had the idea for the study and designed it. I. A. B. and D. K. M.
performed the literature search, study selection, extraction of data
 Systematic review
from relevant studies and statistical analysis. M. E. F. wrote the first
draft. I. A. B. and D. K. M. made substantial revisions of the manu-
script. All authors approved the final version of the manuscript.
Transparency declarations
None to declare.
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