microorganisms

Article
The Effectiveness of Combination Therapy for Treating
Methicillin-Susceptible Staphylococcus aureus Bacteremia: A
Systematic Literature Review and a Meta-Analysis
Sara Grillo 1,† , Mireia Puig-Asensio 1,2,3, *,† , Marin L. Schweizer 3,4 , Guillermo Cuervo 1,2 , Isabel Oriol 5 ,
Miquel Pujol 1,2 and Jordi Carratalà 1,2,6

1 Department of Infectious Diseases, Bellvitge University Hospital, Bellvitge Institute for Biomedical
Research (IDIBELL), Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Spain;
[email protected] (S.G.); [email protected] (G.C.);
[email protected] (M.P.); [email protected] (J.C.)
2 Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC; CB21/13/00009),
Instituto de Salud Carlos III, 28029 Madrid, Spain
3 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA;
[email protected]
4 Center for Access and Delivery Research and Evaluation, Iowa City VA Health Care System,
Iowa City, IA 52246, USA
5 Hospital Sant Joan Despí Moisés Broggi, Oriol Martorell 12, 08970 Sant Joan Despí, Spain;
[email protected]
6 Department of Medicine, University of Barcelona, 08007 Barcelona, Spain
* Correspondence: [email protected]; Tel.: +34-932-602487; Fax: +34-932-607637
† These authors contributed equally to this work.
Citation: Grillo, S.; Puig-Asensio, M.;
Schweizer, M.L.; Cuervo, G.; Oriol, I.;
Pujol, M.; Carratalà, J. The Abstract: Background: This meta-analysis aims to evaluate the effectiveness of combination therapy
Effectiveness of Combination for treating MSSA bacteremia. Methods: We searched Ovid MEDLINE, EMBASE, Cochrane CEN-
Therapy for Treating TRAL, and clinicaltrials.gov for studies including adults with MSSA bacteremia. The monotherapy
Methicillin-Susceptible Staphylococcus group used a first-line antibiotic active against MSSA and the combination group used a first-line
aureus Bacteremia: A Systematic antibiotic plus additional antibiotic/s. The primary outcome was all-cause mortality. Secondary out-
Literature Review and a comes included persistent bacteremia, duration of bacteremia, relapse, and adverse events. Random-
Meta-Analysis. Microorganisms 2022,
effects models with inverse variance weighting were used to estimate pooled risk ratios (pRR).
10, 848. https://doi.org/10.3390/
Heterogeneity was assessed using the I2 value and the Cochrane’s Q statistic. Results: A total of
microorganisms10050848
12 studies (6 randomized controlled trials [RCTs]) were included. Combination therapy did not sig-
Academic Editors: Renato Fani and nificantly reduce 30-day mortality (pRR 0.92, 95% CI, 0.70–1.20), 90-day mortality (pRR 0.89, 95% CI,
Célia F. Rodrigues 0.74–1.06), or any-time mortality (pRR 0.91, 95% CI, 0.76–1.08). Among patients with deep-seated
Received: 23 March 2022
infections, adjunctive rifampicin may reduce 90-day mortality (3 studies with moderate-high risk
Accepted: 16 April 2022 of bias; pRR 0.62, 95% CI, 0.42–0.92). For secondary outcomes, combination therapy decreased the
Published: 20 April 2022 risk of relapse (pRR 0.38, 95% CI, 0.22–0.66), but this benefit was not maintained when pooling
RCTs (pRR 0.54, 95% CI, 0.12–2.51). Combination therapy was associated with an increased risk of
Publisher’s Note: MDPI stays neutral
adverse events (pRR 1.74, 95% CI, 1.31–2.31). Conclusions: Combination therapy not only did not
with regard to jurisdictional claims in
published maps and institutional affil-
decrease mortality in patients with MSSA bacteremia, but also increased the risk of adverse events.
iations. Combination therapy may reduce the risk of relapse, but additional high-quality studies are needed.

Keywords: Staphylococcus aureus; methicillin-susceptible; bacteremia; combination therapy; meta-analysis

Copyright: © 2022 by the authors.

Licensee MDPI, Basel, Switzerland.
This article is an open access article 1. Introduction
distributed under the terms and
Staphylococcus aureus is a leading cause of bloodstream infections, with an incidence of
conditions of the Creative Commons
disease burden that has risen in recent decades due to the increase in healthcare procedures
Attribution (CC BY) license (https://
and the use of indwelling devices [1]. Additionally, S. aureus bacteremia (SAB) is associated
creativecommons.org/licenses/by/
with significant morbidity, mortality, and healthcare costs [2].
4.0/).

Microorganisms 2022, 10, 848. https://doi.org/10.3390/microorganisms10050848 https://www.mdpi.com/journal/microorganisms

Microorganisms 2022, 10, 848 2 of 14

Despite the availability of active antibiotics against methicillin-susceptible S. aureus

(MSSA) [3,4] and the sound clinical evidence that adherence to quality-of-care bundle inter-
ventions is associated with better outcomes [5], 30-day mortality is still high, ranging from
15 to 30% [6]. This poor prognosis of SAB has prompted clinicians to look for other strategies
to improve patient outcomes, including the use of combination antibiotic therapies.
Previous in vitro and in vivo experimental studies have shown that certain combina-
tions of antibiotics are associated with increased bactericidal activity, better intracellular
and biofilm penetration, and a lower risk of developing antibiotic resistance during SAB
treatment [7,8]. Thus, patients at the highest risk of mortality or SAB complications (those
with prosthetic devices, endocarditis, or sepsis) might benefit the most from combina-
tion therapy.
To date, the effectiveness of combination therapies to improve SAB prognosis re-
mains controversial. For methicillin-resistant S. aureus (MRSA), a recent meta-analysis has
concluded that beta-lactam therapy combined with vancomycin or daptomycin does not
reduce SAB mortality [9]. For MSSA, the evidence is even more scarce and derived from
studies that have important limitations. Previous meta-analyses have grouped different
end-points of mortality together (all-cause, 30-day, in-hospital mortality) [10–12], included
both S. aureus and streptococcal endocarditis [10], or focused only on rifampin combina-
tions while mixing methicillin-resistant (MRSA) and MSSA infections [11]. In all, it remains
unclear which subgroup of patients benefits the most from combination therapy, or which
antibiotic combinations are the most effective for reducing SAB mortality.
To address these gaps in knowledge and to gain insights into the effectiveness of
combination therapies for treating MSSA bacteremia—which has been associated with
less mortality than MRSA [13]—we conducted this meta-analysis. We assessed whether
different populations (e.g., patients with endocarditis) might benefit from this strategy in
terms of mortality and persistent bacteremia. We also determined the risk of adverse events
that may limit the generalized use of combined therapies.

2. Methods
2.1. Search Strategy
This meta-analysis followed the Preferred Reporting Items for Systematic and Meta-
Analysis (PRISMA) Statement, and it was registered on PROSPERO (number CRD42020163104).
We searched for studies evaluating the efficacy of combination antibiotic therapies for treat-
ing MSSA bacteremia compared to monotherapy.
A health sciences librarian conducted the search by using subject headings and key-
words for Ovid MEDLINE, EMBASE, and Cochrane CENTRAL (Wiley) from database
inception until 29 January 2021 (Supplementary material). We searched clinicaltrials.gov
to detect unpublished studies. The reference lists of included articles were reviewed to
identify additional studies.

2.2. Eligibility Criteria

We applied the following inclusion criteria: (1) the study population consisted of
adults with MSSA bacteremia. Studies with methicillin-susceptible and resistant S. aureus
strains were included if 10–15% of the study population had MRSA infections. This
threshold was chosen to assure that ≥90% of study population received empiric therapy
against MSSA; (2) the study was a randomized controlled trial (RCT), a quasi-experimental
(non-randomized) trial, or an observational study. Non-RCTs were included to improve
generalizability; (3) the monotherapy group used an active antibiotic against S. aureus;
the combination group used the antibiotic administered in monotherapy plus additional
antibiotic/s; and (4) the study reported mortality rates, persistent bacteremia, or duration
of bacteremia. We excluded non-research articles, conference abstracts, and in vitro and
animal studies.
Microorganisms 2022, 10, 848 3 of 14

2.3. Outcomes
The primary outcome was all-cause mortality, which included 30-day, 90-day, or any-
time mortality. Secondary outcomes were persistent bacteremia or duration of bacteremia,
relapse, adverse events, and development of drug resistance.

2.4. Data Extraction and Quality Assessment

Titles and abstracts were screened for eligibility. Two independent researchers re-
viewed full-text articles and abstracted data using a standardized abstraction form. Data
collected included study design and population, number of patients, S. aureus resistance
to methicillin, antibiotics evaluated, and outcomes. We also recorded variables associated
with better SAB survival: echocardiography use, infectious diseases (ID) consultation, and
adherence to quality-of-care bundle interventions [5,14]. Disagreements between reviewers
were resolved by consensus. When two articles had overlapping study populations, the
more comprehensive was included.
The risk of bias for the association between combination therapy and mortality was
assessed using the Cochrane tool for RCTs [15] and the Robins-I tool for observational
studies [16].

2.5. Statistical Analysis

We used random-effects models with inverse variance weighting to estimate pooled
risk ratios (pRR). Studies with no events (outcomes) in either study arm were omitted from
the meta-analysis. For RCTs, intention-to-treat data were used whenever possible. We
grouped studies that assessed 28-day mortality with those reporting 30-day mortality, and
reported combined pRRs. If different endpoints for mortality were reported, we preferably
evaluated 30- and 90-day mortalities. We assessed heterogeneity using the Cochrane Q
statistic and the I2 test. Publication bias was assessed through visual inspection of funnel
plots and the Egger test. For mortality, we performed subgroup analyses based on a priori
selected variables: study design, antibiotic in combination, source of infection, and indi-
cation of the combination therapy (persistent bacteremia vs. early therapy). Deep-seated
infections included osteoarticular infections, endocarditis, deep-seated abscesses, or foreign
body infections. Statistical analyses were performed using the Cochrane Review Manager
(RevMan, version 5.3), Comprehensive Meta-Analysis Version 3 software (Englewood, NJ,
USA), and Excel 2007.

3. Results
We screened 2054 articles and included 12 studies that met the inclusion criteria
(Figure 1). One study had zero outcomes in both study arms, and it was included in the
systematic literature review but not in the meta-analysis [17]. Table 1 summarizes the
characteristics of included studies. There were six RCTs [17–22] and six observational
studies [23–28]. Six studies were multicentric (≥2 hospitals) [18–20,22–24] and five studies
were published before 2000 [17,20,21,25,28].

3.1. Study Groups

In the monotherapy group, beta-lactams (antistaphylococcal penicillins, first-generation
cephalosporins) were the main antibiotics used. Two studies including ≤11% of MRSA
bacteremias also used vancomycin, teicoplanin, linezolid, or daptomycin [18,23]. In four
studies, the monotherapy group comprised different types of antibiotics against MSSA and
included a few patients receiving an antibiotic that was not the optimal standard of care
(i.e., vancomycin, ceftriaxone, or clindamycin) [19,23,24,28].
Five studies evaluated the combination therapy with aminoglycosides [17,20,21,25,28],
three with rifampicin [18,19,24], two with daptomycin [22,26], and one with vancomycin [27].
One study described two separate analyses for patients who received combination therapy
with levofloxacin and a post-hoc analysis of patients with a deep-seated focus who received
additional rifampicin [19]. One study was classified in the rifampicin group despite includ-
 Microorganisms 2022, 10, 848 4 of 14

ing a small proportion of patients (19%) who received fosfomycin in combination [23]. Also,
Microorganisms 2022, 10, x FOR PEER REVIEW
two studies including >70% of patients with a deep-seated focus used rifampicin, fluoro- 4 of 16
quinolones, or aminoglycosides along with the antibiotics in the monotherapy/combination
groups [19,24].

Figure 1. Flowchart of the selection of the studies.

Figure 1. Flowchart of the selection of the studies.

Microorganisms 2022, 10, 848 5 of 14

Table 1. Main characteristics of the studies included.

Antibiotic/s Reason for Duration Sample Size Outcomes Assessed Adjusted for
Author, Year Study Design; n◦ Study Population Monotherapy Added in the Starting the of the (Combination/
Country a of Hospitals Group Duration of Persistent Adverse the Following
Combination Combination Combination Monotherapy Mortality Relapse Confounders:
Group b Therapy Therapy c Groups) Bacteremia Bacteremia Events
Yes, death
GEN 3-5 Patients who during the
Watanakunakorn, Cohort study; 1 SAB and endocarditis OXA/PEN/CFZ had been 2–3 weeks 40 (15 vs. 25) No No No Nephrotoxicity None
1977, US (possibly MSSA) mg/kg/day 6 weeks of
treated recently
treatment
Nephrotoxicity,
Yes, all-cause drug-induced
Intravenous drug users mortality None,
Abrams, GEN 80 After hepatitis, study groups
RCT; 1 with MSSA bacteremia OXA or CFZ mg/8 h 2 weeks PP 25 (12 vs. 13) (end-point of No No No
1979, US randomization leukopenia,
and endocarditis assessment well-balanced
not reported) drug fever
and rash.
GEN added
because of lack
of prompt Yes, all-cause
clinical mortality
Rajashekaraiah, MSSA bacteremia OXA/PEN/CFZ GEN 4.5 No No No No None
1980, US Cohort study; 1 and endocarditis 4–6 weeks mg/kg/day response At least 7 days 33 (21 vs. 12) (end-point of
Combination assessment
started ≤ 48 h not reported)
after starting
treatment

Korzeniowski, SAB and native valve GEN 3 After

RCT; 1 endocarditis PEN 6 weeks 2 weeks PP 78 (35 vs. 43) Yes, 30-day Yes No No Nephrotoxicity None
1982, US mg/kg/8 h randomization
(possibly MSSA)
Intravenous drug users Yes, death None,
Ribera, RCT; 1 GEN 1 After No Yes Yes study groups
1996, Spain with right-sided OXA 14 days mg/kg/8 h randomization 7 days PP 74 (36 vs. 38) during Nephrotoxicity
MSSA endocarditis treatment well-balanced
Yes, liver
enzyme
LVX 500 mg elevations,
BL+/− AMG None,
Ruotsalainen, once or b.i.d After 381 (191 vs. Yes, 30 and Clostridoides study groups
RCT; 13 MSSA bacteremia (If endocarditis) according 42 days (28–58) No No No
2006, Finland +/−RIF randomization 190) 90-days difficile, and well-balanced
to weight. allergic
reactions
evaluated.
Post-hoc analysis BL+/− AMG
Ruotsalainen, MSSA bacteremia with LVX+ RIF 450 NR No No No No NR
2006, Finland of a prospective deep seated infection (If endocarditis) or 600 mg/day Unknown 331 (265 vs. 66) Yes, 90-day
cohort; 13 +/−LVX
Age, severity of
OXA (58%), Short illness, ID
Retrospective CXM, CRO, consultation,
Forsblom, MSSA bacteremia and RIF 450 or (1–13 days) Yes, 30 and endocarditis,
NR Long 357 (261 vs. 96) No No Yes No
2015, Finland cohort; 13 deep infection focus VAN or CLI d 600 mg/day 90-days ultimately-
+/−FLQ/AMG (≥14 days) rapidly
fatal disease
NR, but
combination Charlson score,
Park, Retrospective e 2.8 days Pitt score,
MSSA bacteremia BL VAN was an 92 (46 vs. 46) Yes, 30-day Yes No No Nephrotoxicity
2017, Korea matched cohort; 1 (2.1–3.8) white blood
empirical cell count
treatment
Microorganisms 2022, 10, 848 6 of 14

Table 1. Cont.

Antibiotic/s Reason for Duration Sample Size Outcomes Assessed Adjusted for
Author, Year Study Design; n◦ Study Population Monotherapy Added in the Starting the of the (Combination/
Country a of Hospitals Group Duration of Persistent Adverse the Following
Combination Combination Combination Monotherapy Mortality Relapse Confounders:
Group b Therapy Therapy c Groups) Bacteremia Bacteremia Events
Yes, all
type. Serious
Patients with SAB who adverse events,
have received ≤ 96 h of None,
Thwaites, OXA (83%), RIF 600 or After 12.6 days 708 (370 vs. Yes, re- drug- study groups
RCT; 29 active antibiotic 900 mg/day Yes, 90-day Yes No currence
2018, UK treatment (94% MSSA;
VAN or TEC randomization (6.0–13.2) 388) modifying well-balanced
6% MRSA bacteremia) adverse events,
drug interac-
tions
NR; but
combination
Post-hoc analysis was Age, Pitt score,
Patients with MSSA DAP administered
Grillo, of a prospective bacteremia who BL 9 days (4–15) 350 (136 vs. Yes, 7, 30 and No Yes No No
2019, Spain 10 mg/kg/day for ≥72 h and 214) 90-days source of
cohort; 1 survived > 48h started within infection
the first 4 days
of treatment

RIF NR;
Post-hoc analysis SAB with deep-seated combination
Rieg, OXA, DAP, (450 mg/12 h) 578 (313 vs. Yes, 30 and Age, Charlson,
of a prospective infection (89% MSSA; started within 23 days (13–33) No No Yes No
2020, Germany VAN, LIN [77.3%] or FOS 14 days after 265) 90-days severe sepsis
cohort; 2 11% MRSA bacteremia) (5 g/8 h iv) SAB onset
Nephrotoxicity,
Patients with MSSA hepatotoxicity,
None,
Cheng, Double-blind bacteremia with ≤72 h DAP After Yes, 30 and rhabdomlyoli- study groups
from first positive BL 5 days PP 104 (53 vs. 51) Yes No Yes
2020, Canada RCT; 2 6 mg/kg/day randomization 90-days sis within well-balanced
blood culture 5 days
of enrollment
aAbbreviations: SAB, Staphylococcus aureus bacteremia; RCT, randomized controlled trial; PP, per protocol; IVDU, intravenous drug users; OXA, oxacillin; PEN, penicillin; CFZ, cefazolin;
GEN, gentamycin; BL, beta-lactams; AMG, aminoglycosides; RIF, rifampicin; LVX, levofloxacin; CMX, cefuroxime; CRO, ceftriaxone; CLI, clindamycin; FLQ, fluoroquinolones; DAP,
daptomycin; VAN, vancomycin; TEC, teicoplanin; LIN, linezolid; FOS, fosfomycin; MSSA, methicillin-susceptible S. aureus. NR: not reported. b Antibiotic added to the monotherapy
backbone. c Data presented as median (IQR) otherwise specified. d When multiple types of antibiotics are listed, the most frequently administered is highlighted in bold and the
percentage is indicated in parenthesis. e Dose of vancomycin was not reported.
Microorganisms 2022, 10, 848 7 of 14

3.2. Start of Combination Therapy

Among studies with available data, eight reported early administration of combi-
nation therapy. That is, combination therapy was initiated ≤72 h after blood sample
collection, ≤96 h after starting active treatment [18,22,25–27], or after the suspicion of
endocarditis [17,20,21]. In two studies evaluating the combination with rifampicin, this treat-
ment was started later, within seven [19] or fourteen days [23] after blood sample collection.

3.3. Sources of Infection

Most studies evaluated patients with S. aureus bacteremia, regardless of the source of
infection. However, studies assessing the combination with aminoglycosides focused on
patients with endocarditis [17,20,21,25,28]. Two studies evaluating the combination with
rifampicin and one post-hoc analysis restricted their analyses to patients with deep-seated
infections or with foreign devices [19,23,24]. The remaining five studies included a variable
proportion of patients with endocarditis (4% to 23%) [18,19,22,23,26] or with prosthetic
materials (6% to 34%) [18,19,22,26]. In one study evaluating the combination therapy with
daptomycin, 7% of patients had pneumonia [22] (Table 1; Supplementary Table S1).

3.4. Compliance with Good Clinical Practices

One RCT evaluating the combination therapy with daptomycin reported that all pa-
tients received the optimal standard of care, with removal of intravascular devices, perfor-
mance of echocardiogram, and ID consultation [22]. The remaining studies did not list com-
plete compliance with these quality-of-care indicators (Supplementary Table S1). Eight re-
ported that all or nearly all patients (>79%) [17–19,23–26,28] were followed by an ID special-
ist, but only four mentioned rates of source control as part of SAB management [18,19,23,26]
or indications for an echocardiogram [21,26].

3.5. Risk of Bias

All observational studies had moderate-high risk of bias when assessed by the Robins-
I tool (Supplementary Figures S1 and S2). Confounding bias was frequent, probably
because combination therapy was commonly administered in more severely ill patients.
Four studies used appropriate methods to control for confounding factors of mortality
(Table 1) [23,24,26,27].
Among the RCTs, 36% of the participants in a double-blind study assessing rifampicin
knew they were receiving the study drug [18].
Six studies assessed duration of bacteremia or persistent bacteremia [18,20–22,26,27],
but only four obtained follow-up blood cultures at scheduled times [18,20–22]. The two
best designed RCTs performed their analyses with competing risk analysis [18] or with a
time-to-event analysis [11].

3.6. Effectiveness of Combination Therapy

Eleven studies were included in the meta-analysis: all reported mortality rates, three
duration of bacteremia [20,22,27], and two persistent bacteremia [21,26]. Five studies
reported relapse rates [17,21–24] and five drug-related adverse events [18,20–22,27]. One
study assessed the development of drug resistance during treatment [18]. Study outcomes
are displayed in Supplementary Table S2.

3.6.1. Mortality
All-cause mortality was 14.4% (216/1503) in the combination group and 16.1% (215/1339)
in the monotherapy group. Pooled results did not show a significant reduction in the risk
of 30-day (seven studies; pRR 0.92, 95% CI, 0.70–1.20, I2 = 26%), 90-day (six studies;
pRR 0.89, 95% CI, 0.74–1.06, I2 = 27%), or any-time mortality (11 studies; pRR 0.91, 95% CI,
0.76–1.08, I2 = 0%) in patients who received combination therapy compared to monotherapy
(Figure 2; Table 2). These results were consistent when studies with late or unknown start of
combination therapy or when studies published before 2000 were excluded. Heterogeneity
 All-cause mortality was 14.4% (216/1503) in the combination group and 16.1%
(215/1339) in the monotherapy group. Pooled results did not show a significant reduction
in the risk of 30-day (seven studies; pRR 0.92, 95% CI, 0.70–1.20, I2 = 26%), 90-day (six
studies; pRR 0.89, 95% CI, 0.74–1.06, I2 = 27%), or any-time mortality (11 studies; pRR 0.91,
Microorganisms 2022, 10, 848 8 of 14
95% CI, 0.76–1.08, I2 = 0%) in patients who received combination therapy compared to
monotherapy (Figure 2; Table 2). These results were consistent when studies with late or
unknown start of combination therapy or when studies published before 2000 were
was excluded.
low. The funnel plot for 30-day
Heterogeneity and
was low. Theany-time mortality
funnel plot was asymmetrical
for 30-day and any-time and there was
mortality
was asymmetrical
evidence of publication bias (Supplementary Figures S3–S5).
and there was evidence of publication bias (Supplementary Figures S3–S5).

30-day mortality

Relapse or recurrence

Drug-adverse events

Figure 2. Effectiveness of combination therapy on main outcomes.

Figure 2. Effectiveness of combination therapy on main outcomes.
Subgroup analyses performed separately for RCTs and observational studies did not
yield different results, but heterogeneity was moderate-high among observational studies
(30-day mortality: I2 = 42%; 90-day mortality: I2 = 68%) (Table 2). To investigate causes
of heterogeneity, we pooled observational studies that were adjusted for confounding
factors and RCTs with well-balanced characteristics between study groups. The hetero-
geneity decreased and results were consistent with the main findings, with no reductions
in 30- and 90-day mortality with combination therapy (pRR 1.04, 95% CI, 0.67–1.60; I2 = 0%
and pRR 0.96, 95% CI, 0.78–1.19; I2 = 13%, respectively).
We next hypothesized that the source of SAB might influence the effectiveness of
combination therapy. The meta-analysis of three studies including patients with deep-
seated infections suggested that combination therapy with rifampicin might be associated
with decreased 90-day mortality (pRR 0.62, 95% CI, 0.42–0.92), but the heterogeneity was
high: I2 = 73% (Table 2). These studies had a moderate-high risk of bias, and they were of
lower quality. Also, the pooled analysis of studies including patients with endocarditis
did not demonstrate that the combination therapy with aminoglycosides reduced any-time
mortality (four studies: pRR 1.17, 95% CI, 0.64–2.16; I2 = 0%). These studies focused on
patients with native valve endocarditis, in particular right-sided endocarditis (30–100% of
participants) in drug users. Other subgroup analyses according to the source of infection
were not possible.
Microorganisms 2022, 10, 848 9 of 14

Table 2. Summary of the subgroup analyses performed.

N◦ . of Studies N◦ . of Patients
Subgroup Analyses References
(Combination/Monotherapy)
Pooled Risk Ratio (95% CI) I2 Test

30-day mortality All studies 7 [19,20,22–24,26,27] 1043/894 0.92 (0.70–1.20) 26%

RCTs 3 [19,20,22] 287/276 1.08 (0.70–1.67) 0%
Observational studies 4 [23,24,26,27] 756/618 0.85 (0.60–1.22) 42%
Adjusted observational studies + well-balanced 3 [19,22,27] 290/287 1.04 (0.67–1.60) 0%
RCTs
Early administration of combination therapy 4 [20,22,26,27] 278/346 1.31 (0.88–1.95) 0%
After excluding studies published before 2000 6 [19,22–24,26,27] 1000/859 0.88 (0.69–1.13) 18%
90-day mortality All studies 6 [18,19,22–24,26] 1336/1179 0.89 (0.74–1.06) 27%
RCTs 3 [18,19,22] 632/611 0.93 (0.72–1.20) 0%
Observational studies 3 [23,24,26] 704/568 0.86 (0.60–1.22) 68%
Adjusted observational studies + well-balanced 5 13%
RCTs [18,19,22,23,26] 1075/1083 0.96 (0.78–1.19)
After excluding studies with late start of
3 [18,22,26] 577/635 1.07 (0.84–1.37) 0%
combination therapy
All participants with deep-seated infections
3 [19,23,24] 833/420 0.62 (0.42–0.92) 73%
(rifampicin) a
Any-time mortality b All studies 11 [18–28] 1503/1339 0.91 (0.76–1.08) 0%
RCTs 6 [18–22,25] 732/696 1.01 (0.78–1.31) 0%
Observational studies 5 [23,24,26–28] 771/643 0.86 (0.64–1.15) 25%
After excluding studies with late start of
7 [18,20–22,25–27] 723/766 1.09 (0.85–1.41) 0%
combination therapy
After excluding studies published before 2000 7 [18,19,22–24,26,27] 1388/1229 0.89 (0.74–1.08) 5%
All participants with endocarditis
4 [20,21,25,28] 115/110 1.17 (0.64–2.16) 0%
(aminoglycosides) c
≥30% left-sided endocarditis (aminoglycosides) 3 [20,25,28] 79/72 1.12 (0.60–2.11) 0%
Relapse d All studies 5 [18,21–24] 749/598 0.38 (0.22–0.66) 0%
Excluding Thwaites study that used a different
4 [21–24] 379/210 0.45 (0.24–0.83) 0%
definition (recurrence)
RCTs 3 [18,21,22] 459/477 0.54 (0.12–2.51) 46%
Observational studies 2 [23,24] 290/121 NA
Drug adverse-events d Any type of antibiotic adverse-event 5 [18,20–22,27] 539/554 1.74 (1.31–2.31) 0%
After excluding studies published before 2000 3 [18,22,27] 460/482 1.69 (1.24–2.30) 0%
Nephrotoxicity or AKI 4 [20–22,27] 169/166 1.81 (1.17–2.79) 0%
Abbreviations: AKI, acute kidney injury; CI, confidence interval; RCT, randomized controlled trial; NA, not applicable. a All these studies compared the use of beta-lactams in
monotherapy with beta-lactams plus rifampicin. b When different definitions of mortality were available for one study (e.g., 30-day mortality, 90-day mortality, mortality during
antibiotic treatment), 30-day mortality was preferably chosen for pooled analyses. We hypothesized that at later time points, the evaluation of treatment-related effectiveness might be
less accurate given the increasing effect of patient’s baseline comorbidities on mortality. c All these studies compared the use of beta-lactams in monotherapy with beta-lactams plus
gentamicin. They primarily focused on patients with native valve endocarditis, in particular right-sided endocarditis (30-100% of participants) in drug users. d None of these studies
adjusted their analyses when evaluating the outcome relapse or adverse event.
Microorganisms 2022, 10, 848 10 of 14

3.6.2. Duration of Bacteremia

Three studies [20,22,27] reported the mean or median duration of bacteremia, but
only two provided the standard deviations needed to calculate the standardized mean
difference [20,27]. Therefore, we could not meta-analyze these data.
The role of combination therapy to increase the rapid killing of MSSA is unclear.
With regard to aminoglycosides, one RCT of 78 patients with native valve endocardi-
tis (68.8% right-sided) showed that adding gentamycin during the first two weeks of
therapy was associated with faster eradication of SAB (mean 2.9 vs. 3.8 days) [20]. How-
ever, other RCTs assessing the combination with rifampicin [18] or daptomycin (mean
2.0 vs. 1.7 days) [22], and a small cohort study evaluating vancomycin (median 2.8 vs.
2.2 days) [27], did not find an association between combination therapy and duration of
bacteremia.

3.6.3. Persistent Bacteremia

Two studies assessed persistent bacteremia, namely positive blood cultures for ≥3 days
or at 4 days [21,26], and they showed contradictory results. One RCT of 90 patients with
MSSA right-sided native valve endocarditis did not find that combination therapy with
aminoglycosides during the first seven days of therapy reduced persistent bacteremia (2.6%
[1/38] vs. 0% [0/36]) [21]. This study had limited statistical power for this outcome. Con-
versely, an observational study found that persistent bacteremia was more frequent using
daptomycin in combination compared to monotherapy (26.7% [35/131] vs. 9.1% [18/197];
p < 0.001) [26]. However, this result may reflect unadjusted imbalances between study
groups, with more severely ill patients receiving the combination therapy.

3.6.4. Relapse or Recurrence

Five studies, three of which explored rifampicin combinations, reported SAB relapse
by demonstrating the bacteriological recovery of S. aureus with the same resistance pattern
from the bloodstream [22–24] or from a sterile site during follow-up [18]. One study
required the comparison of S. aureus isolates by phage-typing [21]. The time point of
relapse measurement varied across studies: within 90 days [22,24] or 6 months [21,23]. One
study used the term “recurrence,” defined as the isolation of the same strain of S. aureus
from a sterile site after seven days of improvement [18].
The overall relapse/recurrence rates were 2.0% (15/749) for patients with combination
therapy and 6.0% (36/598) for those who received monotherapy. Pooled results suggested
that combination therapy was significantly associated with a decreased risk of relapse
(five studies; pRR 0.38, 95% CI, 0.22–0.66; I2 = 0%), but there was possible publication
bias (Supplementary Figure S6). Similar conclusions were obtained for studies evaluating
rifampicin (three studies; pRR 0.32, 95%CI CI, 0.18–0.58; I2 = 0%), although two studies
had a moderate-high risk of bias [23,24]. Importantly, subgroup analyses performed on
better designed RCTs showed differing results, with no significant association between
combination therapy and relapse (three studies; pRR 0.54, 95% CI, 0.12–2.51), although
heterogeneity was moderate (I2 = 46%) (Table 2).

3.7. Drug-Related Adverse Events

Combination therapy was significantly associated with adverse events (five studies;
pRR 1.74, 95% CI, 1.31–2.31; I2 = 0%) (Table 2), in particular with nephrotoxicity, which was
mainly assessed in studies including nephrotoxic drugs (four studies; pRR 1.81, 95% CI,
1.17–2.79; I2 = 0%). Conclusions did not change after excluding studies published before
2000 (three studies; pRR 1.69, 95% CI, 1.24–2.30; I2 = 0%) [18,22,27]. The funnel plot showed
possible evidence of publication bias (Supplementary Figure S7). One study evaluated
Clostridioides difficile diarrhea and concluded that there were no significant differences
between the study groups [24]. Other adverse events were rarely reported (Table 1).
Microorganisms 2022, 10, 848 11 of 14

3.8. Effectiveness per Type of Antibiotic in Combination

Detailed descriptions of studies and pooled analyses per type of antibiotic (aminogly-
cosides and rifampicin) are summarized in the Supplementary material.

4. Discussion
In this meta-analysis, we found that patients with MSSA bacteremia who received
combination therapy not only did not present a lower risk of all-cause mortality but also
presented an increased risk of adverse events. Although our data suggest that combination
therapy reduces the risk of relapse and that patients with deep-seated infections or im-
planted foreign devices may benefit from combinations with rifampicin, additional studies
are needed to better define recommendations for its use.
Focusing on specific combinations, the evidence does not favor combination therapy
with aminoglycosides. The studies included were mostly performed in patients with right-
sided endocarditis, but none of them demonstrated that the addition of aminoglycosides
decreased mortality rates. It is possible that patients who receive aminoglycosides expe-
rience faster clearance of MSSA bacteremia [20], but this benefit does not affect mortality,
and it is associated with a greater risk of nephrotoxicity. Thus, our results support current
guidelines [29,30] that do not recommend the use of low-dose gentamycin for treating SAB,
even in patients with native valve endocarditis.
Rifampicin is an appealing option as a combination therapy. It has good activity
against S. aureus and its biofilm, being useful for treating hardware-associated infections.
Our results suggest that combinations including rifampicin may reduce 90-day mortality
and relapse in bacteremic patients with deep-seated infections and implanted foreign body
devices. This evidence is mainly derived from observational studies with a moderate-
high risk of bias, but the results are plausible given rifampicin’s mechanism of action.
Indeed, combination therapy with rifampicin is recommended in S. aureus prosthetic
joint infections and prosthetic valve endocarditis [30,31]. However, there is no evidence
supporting its use in bacteremic patients who do not have these sources of infection. First,
a well-conducted RCT (the ARREST trial) including 758 patients with a low proportion
of prosthetic device infections did not show that adding rifampicin provided any benefit
in reducing mortality or shortening the duration of bacteremia [18]. Second, the early
administration of rifampicin during the bacteremic phase of the infection may promote the
development of resistance [32]. The appropriate time to start rifampicin combinations in
bacteremic patients is an unresolved issue.
Few of the studies assessed other combination therapies. According to one small
cohort study [27], beta-lactams plus vancomycin did not reduce SAB mortality or the
duration of bacteremia. However, the use of beta-lactams with vancomycin may play a
role as empirical therapy for covering both methicillin-susceptible and resistant strains.
The use of vancomycin for MSSA bacteremia is associated with poorer outcomes than beta-
lactams [33]. Consequently, some clinicians might opt to use this empirical combination
when there is a suspicion of staphylococcal bacteremia and S. aureus susceptibility is not
known [4].
Similarly, the early combination of beta-lactams with daptomycin is not warranted.
Neither of the included studies found significant differences in mortality, duration of
bacteremia, or relapse when adding daptomycin within the first four days of SAB treat-
ment [22,26]. These results contrast with reports describing successful outcomes when
using ceftaroline plus daptomycin as salvage therapy, especially in patients with persistent
MRSA bacteremia [34–36]. Although an experimental model of infective endocarditis
suggested that cloxacillin plus daptomycin have a synergistic effect [37], further clinical
studies are needed.
Finally, reports or case-series have described the use of two beta-lactams such as
ertapenem plus cefazolin as salvage therapy for persistent MSSA bacteremia [38,39]. How-
ever, there are no RCTs assessing the effectiveness of this combination for SAB treatment.
Microorganisms 2022, 10, 848 12 of 14

This meta-analysis shows that the use of combination therapies comes at a cost of
an increased risk of adverse events. In the ARREST trial [18], for example, the addition
of rifampicin was associated with antibiotic adverse events and drug–drug interactions,
even though 11% of screened patients were not enrolled because of pre-existing liver
disease and the risk of drug interactions. Interestingly, none of the studies evaluated the
risk of colonization for multi-drug resistant bacteria and only one study mentioned no
differences in C. difficile diarrhea between study arms. Future studies should evaluate
both effectiveness and adverse events; conditions that may impact the extended use of
antibiotic combinations.
Our meta-analysis has certain limitations. The studies we included differed in sources
of S. aureus bacteremia, outcome definitions, type and duration of combinations, and the
dose of antibiotics evaluated. When possible, we pooled studies with similar characteristics
to provide more reliable results, but study populations were heterogeneous. Furthermore,
the impact of race and gender was not examined in subgroup analyses, and these factors
may have affected treatment response. Some observational studies had selection biases
that were often not properly addressed and this might have biased the results towards the
null. However, we performed subgroup analyses of studies that adjusted for confounding
factors and well-balanced RCTs yielding similar conclusions to our overall pooled analysis.
Finally, most studies did not report data regarding adherence to good-quality-of-care
indicators [5] or the rates of source control. To improve the quality of research, future
studies should use standardized endpoints (probably earlier timepoints of mortality to
optimize antibiotic combination assessment), focus on high-risk patients (e.g., patients with
implanted foreign devices), and describe the compliance with good clinical practices to
ensure the best management of SAB [40].
In conclusion, the currently available data do not support the use of combination
therapy to reduce mortality in all patients with MSSA bacteremia. Further, this therapeutic
strategy is associated with an increased risk of drug-related adverse events. Patients
with deep-seated infections or implanted foreign devices may benefit from a late start of
combinations with rifampicin, but more studies are needed to define recommendations
on its use. Well-designed multicenter trials with large samples and with patient-risk
stratification for evaluating the combination therapy are urgently needed.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/microorganisms10050848/s1, Figure S1: Risk of bias for obser-
vational studies; Figure S2: Risk of bias for randomised controlled trials; Figure S3: Funnel plot for
30-day mortality; Figure S4: Funnel plot for 90-day mortality; Figure S5: Funnel plot for any-time
mortality; Figure S6: Funnel plot for relapse or recurrence; Figure S7: Funnel plot for drug adverse-
events; Table S1: Detailed description of study population; Table S2: Outcomes. References [41,42]
cited in Supplementary Materials.
Author Contributions: S.G. and M.P.-A. had full access to all the data in the study and take re-
sponsibility for its integrity and the accuracy of its analysis. J.C., S.G. and M.P.-A. conceived and
designed the study. S.G. and M.P.-A. collected the data and wrote the manuscript. M.P.-A. and M.L.S.
performed statistical analyses. G.C., I.O. and M.P. critically reviewed the manuscript for important
intellectual content. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by Plan Nacional de I+D+i 2017–2021 and Instituto de Salud
Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio
de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases
(REIPI RD16/0016/0005; RD16/0016/0002; RD16/0016/0001), and it was co-financed by the Eu-
ropean Development Regional Fund ‘A way to achieve Europe’, Operative program Intelligent
Growth 2014–2020.
Institutional Review Board Statement: Ethical review and approval were waived for this study, due
to the nature of its design: review of previously published studies.
Informed Consent Statement: Not applicable.
Microorganisms 2022, 10, 848 13 of 14

Data Availability Statement: Not applicable.

Acknowledgments: We thank the CERCA Programme/Generalitat de Catalunya for institutional
support. We thank Heather Healy, Clinical Education Librarian at the Hardin Library for the Health
Sciences, for her help with search strategies.
Conflicts of Interest: The authors declare no conflict of interest.

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