antibiotics

Article
Comparison between Ceftriaxone and Sulbactam-Ampicillin
as Initial Treatment of Community-Acquired Pneumonia:
A Systematic Review and Meta-Analysis
Hideo Kato 1,2,3 , Mao Hagihara 1,4 , Nobuhiro Asai 1 , Jun Hirai 1 , Yuka Yamagishi 1 , Takuya Iwamoto 2,3
and Hiroshige Mikamo 1, *

1 Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute 480-1195, Japan
2 Department of Pharmacy, Mie University Hospital, Tsu 514-8507, Japan
3 Department of Clinical Pharmaceutics, Division of Clinical Medical Science,
Mie University Graduate School of Medicine, Tsu 514-8507, Japan
4 Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University Hospital,
Nagakute 480-1195, Japan
* Correspondence: [email protected]; Tel.: +81-0561611842

Abstract: Current guidelines recommend the use of ceftriaxone and sulbactam-ampicillin for the
initial treatment of community-acquired pneumonia (CAP). However, there are no clear data on these
guidelines. Therefore, this systematic review and meta-analysis aims to evaluate the effectiveness of
ceftriaxone and sulbactam-ampicillin in the initial treatment of CAP. The Embase, Scopus, PubMed,
Citation: Kato, H.; Hagihara, M.; Ichushi, and Cumulative Index to Nursing and Allied Health Literature databases were systematically
Asai, N.; Hirai, J.; Yamagishi, Y.; searched from inception to July 2022. The studies included patients who received ceftriaxone or
Iwamoto, T.; Mikamo, H. sulbactam-ampicillin as the initial antibiotic therapy for CAP. The mortality and clinical cure rates
Comparison between Ceftriaxone were evaluated. Of the 2152 citations identified for screening, four studies were included. Results
and Sulbactam-Ampicillin as Initial
of the pooled analysis indicated no significant differences in the mortality and clinical cure rates
Treatment of Community-Acquired
between patients treated with ceftriaxone and those treated with sulbactam-ampicillin (mortality,
Pneumonia: A Systematic Review
odds ratio [OR]: 1.85, 95% confidence interval [CI]: 0.57–5.96; clinical cure rate, OR: 1.08, 95% CI:
and Meta-Analysis. Antibiotics 2022,
0.18–6.44). This study supports the guidelines for CAP treatment, though further studies are needed
11, 1291. https://doi.org/10.3390/
antibiotics11101291
to obtain a deeper understanding.

Academic Editors: Anastasia Keywords: meta-analysis; ceftriaxone; sulbactam-ampicillin; community-acquired pneumonia

Kotanidou, Sotirios Tsiodras,
Paraskevi C. Fragkou and
Charalampos D. Moschopoulos

Received: 30 August 2022 1. Introduction

Accepted: 20 September 2022 Community-acquired pneumonia (CAP) is an infectious inflammation of the lung
Published: 22 September 2022 parenchyma and remains an important disease threatening human health. The overall
Publisher’s Note: MDPI stays neutral incidence rate of CAP ranges from 1.07 to 14 per 1000 persons/year [1–3]. In the United
with regard to jurisdictional claims in States, CAP accounts for more than 4.5 million outpatients and emergency room visitors [4].
published maps and institutional affil- Moreover, the annual total cost of treating CAP is USD 250 million [5]. Currently, CAP
iations. treatment is faced with several problems and challenges associated with high mortality
and economic burden [5,6].
CAP is primarily treated with antibiotic therapy. The appropriate selection of an-
tibiotics at the early stage of infection is key to improving the efficacy of therapy. Initial
Copyright: © 2022 by the authors. antibiotics are empirically selected on the basis of pathogen distribution and antimicrobial
Licensee MDPI, Basel, Switzerland. resistance. Streptococcus pneumoniae and Haemophilus influenzae are commonly isolated
This article is an open access article
from patients with CAP in many countries [7]. However, the identification of causative
distributed under the terms and
pathogens is difficult in patients with CAP, and the percentage has been reported as 40% [8].
conditions of the Creative Commons
Therefore, the optimal antibiotic for CAP treatment is still unclear.
Attribution (CC BY) license (https://
Various guidelines recommend ceftriaxone and sulbactam-ampicillin as first-line
creativecommons.org/licenses/by/
antibiotics for CAP [9–11]. Ceftriaxone has a spectrum of activity against microorganisms,
4.0/).

Antibiotics 2022, 11, 1291. https://doi.org/10.3390/antibiotics11101291 https://www.mdpi.com/journal/antibiotics

Antibiotics 2022, 11, 1291 2 of 8

which are the predominant pathogens in aspiration pneumonia, that is similar to that of
sulbactam-ampicillin [12]; meanwhile, ceftriaxone does not target the full spectrum of oral
anaerobes that cause aspiration pneumonia [13,14].
Most patients with CAP are treated for mild CAP at the outpatient and primary care
clinics [15]. Ceftriaxone has been reported as the most commonly used antibiotic for CAP
treatment because of its less frequent administration, lack of requirement for initial dose
adjustment according to renal impaired functions, and status as an alternative therapy for
patients who are allergic to penicillin [16,17]. However, clinical efficacy of ceftriaxone for
CAP treatment is controversial because of the limited data.
Only one meta-analysis has provided evidence of the effectiveness of antibiotics in the
treatment of CAP [18]. However, this meta-analysis did not include studies that compared
ceftriaxone with sulbactam-ampicillin. Thus, it remains unclear whether ceftriaxone or
sulbactam-ampicillin is a more effective treatment for CAP. To date, three retrospective
studies have compared the efficacy of ceftriaxone with that of sulbactam-ampicillin in the
treatment of CAP [19–21]. Moreover, a prospective study was recently published [22].
Hence, this systematic review and meta-analysis aimed to evaluate the efficacy of
ceftriaxone and sulbactam-ampicillin as initial treatment for CAP.

2. Results
2.1. Systematic Review
The systematic review of electronic databases resulted in the identification of 2152 arti-
cles. After reviewing the titles and abstracts, 1842 articles were deemed ineligible. A full-
Antibiotics 2022, 11, x FOR PEER REVIEW 3 of 10
text review of 16 articles was performed. Figure 1 shows the full list of exclusion criteria.
Eventually, four studies met our inclusion criteria [19–22].

Figure 1. PRISMA flow diagram of the study selection process.

Figure 1. PRISMA flow diagram of the study selection process.

The characteristics of the four studies are summarized in Table 1. All included studies
were conducted in adult Japanese patients. Three were retrospective studies [19–21],
while one was a randomized controlled trial (RCT) [22]. All included studies, except for
one, were conducted in a single center [21]. Two studies reported pneumonia mainly due
to S. pneumoniae and H. influenzae [21,22], while the others did not report the bacteriologi-
Antibiotics 2022, 11, 1291 3 of 8

The characteristics of the four studies are summarized in Table 1. All included studies
were conducted in adult Japanese patients. Three were retrospective studies [19–21], while
one was a randomized controlled trial (RCT) [22]. All included studies, except for one,
were conducted in a single center [21]. Two studies reported pneumonia mainly due to
S. pneumoniae and H. influenzae [21,22], while the others did not report the bacteriological
origins [19,20].

Table 1. Characteristics of the Studies Included in the Meta-Analysis.

Country of Agent Used with

Study Study Design Setting Period No of Patients
Study Dosage
Retrospective
Shinoda Y, January 2013 to SAM, 45; SAM, NR;
observational Single center Japan
2016 [19] May 2013 CRO, 9 CRO, NR
study
Retrospective
Terafarad F, January 2014 to SAM, 20 SAM, 3–6 g/day;
observational Single center Japan
2017 [20] December 2015 CRO, 20 CRO, 2–4 g/day
study
Retrospective September
Hasegawa S, SAM, 400; SAM, NR;
observational Multicenter 2011 to Japan
2019 [21] CRO, 237 CRO, NR
study August 2014
Open-label,
Hamao N, June 2002 to SAM, 139; SAM, 1.5–6.0 g/day;
randomized Single center Japan
2020 [22] June 2008 CRO, 124 CRO, 1–2 g/day
controlled trial
Mean Duration of
Study Mean Age, Years Underlying Disease (%) Pathogen (%)
Therapy, Days
Stroke, 45.5
Shinoda Y, SAM, NR; Overall GPB, 9.9
Alzheimer’s disease, 33.7
2016 [19] CRO, NR Over 80, 72.3% GNB, 55.4
Parkinson’s disease, 12.9
Dementia, 55.0
Terahara F, SAM, NR; SAM, 88; Bedridden status, 30.0
NR
2017 [20] CRO, NR CRO, 81 Cerebrovascular disease, 27.5
Neuromuscular diseases, 7.5
Dementia, 28.9
Mainly
Hasegawa S, SAM, NR; SAM, 82; Bedridden status, 16.3
Streptococcus pneumoniae and
2019 [21] CRO, NR CRO, 82 Cerebrovascular disease, 4.4
Haemophilus influenzae
Neuromuscular diseases, 11.9
S. pneumoniae, 23.2%;
Hamao N, SAM, 7–14; SAM, 63;
NR H. influenzae, 2.3%;
2020 [22] CRO, 7–14 CRO, 61
unknown, 47.1%
CRO, ceftriaxone; GNB, gram-negative bacteria; GPB, gram-positive bacteria; No., number; NR, not reported;
SAM, sulbactam-ampicillin.

The risks of bias in the assessment results are presented in Table 2. The risks of bias
regarding the selection of participants, measurement of exposure, incomplete outcome
data, and selective outcome reporting in all studies were relatively low. The confounding
variables in the study reported by Shinoda showed a high risk of bias [19]. As the study
reported by Hamano was an RCT, the risk of bias was low for all items [22].

Table 2. Risk of bias in the included studies.

Building of Incomplete Selective

Selection of Confounding Measurement
Study Outcome Outcome Outcome
Participants Variables of Exposure
Assessment Data Reporting
Shinoda Y, 2016 [19] Low risk High risk Low risk High risk Low risk Low risk
Terahara F, 2017 [20] Low risk Low risk Low risk High risk Low risk Low risk
Hasegawa S, 2019 [21] Low risk Low risk Low risk High risk Low risk Low risk
Hamao N, 2020 [22] Low risk Low risk Low risk Low risk Low risk Low risk

2.2. Meta-Analysis
The mortality rates extracted from the four studies were 5.6% (22/390) for patients
receiving ceftriaxone and 11.4% (69/604) for those receiving sulbactam-ampicillin [19–22].
 Antibiotics 2022, 11, x FOR PEER REVIEW 6 of 10
Antibiotics 2022, 11, x FOR PEER REVIEW 6 of 10

Antibiotics 2022, 11, 1291 4 of 8

2.2. Meta-Analysis
2.2. Meta-Analysis
The mortality rates extracted from the four studies were 5.6% (22/390) for patients
The mortality rates extracted from the four studies were 5.6% (22/390) for patients
receiving ceftriaxone and 11.4% (69/604) for those receiving sulbactam-ampicillin [19–22].
The mortality
receiving showed and
ceftriaxone no significant difference
11.4% (69/604) between
for those ceftriaxone
receiving and sulbactam-ampicillin
sulbactam-ampicillin [19–22].
The mortality showed no significant difference between ceftriaxone and sulbactam-ampi-
(odds ratio (OR)
The mortality 1.85, 95%,
showed confidence
no significant interval (CI):
difference 0.57–5.96,
between I2 = 51%,
ceftriaxone and Figure 2).
sulbactam-ampi-
cillin (odds ratio (OR) 1.8,595%, confidence interval (CI): 0.57–5.96, I2 = 51%, Figure 2).
cillin (odds ratio (OR) 1.8,595%, confidence interval (CI): 0.57–5.96, I2 = 51%, Figure 2).

Figure 2.
Figure 2. Forest
Forest plot
plot presenting
presentingthe
theodds
oddsratios
ratiosfor
formortality
mortalityininpatients
patientstreated
treatedwith
withsulbactam-
sulbactam-
Figure 2. Forest
ampicillin and plot treated
those presenting
withthe odds ratios
ceftriaxone in for mortality in patients
community-acquired treated with
pneumonia. CI, sulbactam-
confidence
ampicillin
ampicillin and those
those treated
andceftriaxone;
treated with
with ceftriaxone
ceftriaxone in
in community-acquired
community-acquired pneumonia.CI,
pneumonia. CI,confidence
confidence
interval; CRO, M-H, Mantel-Haenszel; SAM, sulbactam-ampicillin; blue square, OR of
interval;
interval;CRO,
CRO, ceftriaxone; M-H, Mantel-Haenszel;
ceftriaxone; M-H, Mantel-Haenszel; SAM, sulbactam-ampicillin;blue
SAM, sulbactam-ampicillin; bluesquare,
square,OR
ORofof
each study; Black rhombus, pooled OR.
each
eachstudy;
study;Black
Black rhombus,
rhombus, pooled
pooled OR.
OR.
The clinical
The clinical cure rates extracted from two studies [20,22] were
were 87.5%
87.5% (126/144)
(126/144)for
The clinical cure
cure rates
rates extracted
extracted from
from two
two studies
studies [20,22]
[20,22] were 87.5% (126/144) for
for
patients
patients receiving
receiving ceftriaxone
ceftriaxone and
and 91.8%
91.8% (146/159)
(146/159) for
for those
those receiving
receiving sulbactam-ampicil-
sulbactam-ampicillin.
patients receiving ceftriaxone and 91.8% (146/159) for those receiving sulbactam-ampicil-
lin. The
The clinical
clinical curecure rate
rate waswascomparable
comparable between ceftriaxone
ceftriaxone and sulbactam-ampicillin
lin. The clinical cure rate was2 comparablebetween
between ceftriaxone and sulbactam-ampicillin
and sulbactam-ampicillin
(OR
(OR 1.08,
1.08, 95%
95% CI:
CI: 0.18–6.44,
0.18–6.44, I
I 2 ==57%,
57%, Figure
Figure 3).
3).
(OR 1.08, 95% CI: 0.18–6.44, I = 57%, Figure 3).
2

Figure 3. Forest plot presenting the odds ratios for clinical cure rates between sulbactam-ampicillin
Figure
Figure
and 3.3. Forest
Forestin
ceftriaxone plot
plot presenting the oddspneumonia.
presenting
community-acquired ratios
ratios for
for clinical
clinical cure
curerates between
ratesinterval;
CI, confidence between sulbactam-ampicillin
sulbactam-ampicillin
CRO, ceftriaxone; M–
and
and ceftriaxone
ceftriaxone in
in community-acquired
community-acquired pneumonia.
pneumonia. CI,
CI,confidence
confidence
H, Mantel–Haenszel; SAM, sulbactam-ampicillin; blue square, OR of each study; interval; CRO,
interval; CRO, ceftriaxone;
ceftriaxone;
black M–
rhombus,M-
H,
H, Mantel–Haenszel;
Mantel-Haenszel;
pooled OR. SAM,
SAM, sulbactam-ampicillin;
sulbactam-ampicillin; blue
blue square,
square, OR
OR ofof each
eachstudy;
study;black
black rhombus,
rhombus,
pooled OR.
pooled OR.
3. Discussion
3.3. Discussion
Discussion
The present meta-analysis showed no significant difference in the incidence of mor-
The present
The present meta-analysis
meta-analysis showed
showed no
no significant
significant difference ininthetheincidence
incidenceofofmor-
tality between patients receiving ceftriaxone and thosedifference
receiving sulbactam-ampicillin. mor-
tality
tality between
between patients
patients receiving ceftriaxone
ceftriaxone and
and those
those receiving
receiving sulbactam-ampicillin.
sulbactam-ampicillin.
The clinical cure rate also showed no significant difference between the two antibiotics. In
Theclinical
The clinical cure rate
rate also
also showed
showedno nosignificant difference between thethe
twotwo antibiotics. In
addition, no significant difference wassignificant
found between difference between
ceftriaxone antibiotics.
and β-lactam/β-lac-
addition,
In addition,nono
significant
significantdifference waswas
difference found
found between
between ceftriaxone
ceftriaxoneandand β-lactam/β-lac-
β-lactam/β-
tamase inhibitor combinations in the treatment of CAP [23,24], which is consistent with
tamase inhibitor
lactamase inhibitorcombinations
combinations inin
the
thetreatment
treatment ofofCAP
CAP [23,24], which isisconsistent with
our findings. Preliminary meta-analysis with limited data [23,24],
shows no which
differenceconsistent with
in clinical
ourfindings.
our findings. Preliminary
Preliminary meta-analysis
meta-analysis withwith limited
limited data
data shows
shows no
no difference
difference ininclinical
clinical
effectiveness. Although the present evidence supports guidelines for the treatment of
effectiveness.Although
effectiveness. Althoughthe the presentevidence
evidence supports guidelines
for for
the the treatment of
CAP, more RCT studies are present
needed to obtain supports guidelines
a deeper understanding. treatment of CAP,
CAP, more
moreClinically, RCT
RCT studies studies are
are needed needed to obtain a deeper understanding.
40%–60% of thetopatients
obtain awith
deeper
CAPunderstanding.
have an unidentified pathogen despite
Clinically, 40–60%
Clinically, 40%–60% of of thepatients
the patientswith
withCAPCAPhavehave an an unidentified pathogen despite
performing bacteriological tests [8], and it remains unclearunidentified
whether initialpathogen
treatmentdespite
is
performing bacteriological
performing bacteriological tests [8], and it remains unclear whether initial treatment is
crucial based on the guidelines. Although previous guidelines have recommended β-lac-is
and it remains unclear whether initial treatment
crucial based
crucial based on
on the
the guidelines.
guidelines. Although
Although previous
previous guidelines
guidelineshavehave
recommended
recommended β-lac-β-
tam/β-lactamase inhibitor combinations, especially sulbactam-ampicillin, for the initial
tam/β-lactamase inhibitor
lactam/β-lactamase inhibitorcombinations,
combinations, especially
especially sulbactam-ampicillin,
sulbactam-ampicillin,for forthe
theinitial
initial
treatment of CAP [25,26], current guidelines have added ceftriaxone as the initial antibiotic
for CAP [9–11]. Therefore, our findings provide robust evidence to support these guidelines
for CAP treatment.
Antibiotics 2022, 11, 1291 5 of 8

The differences in effectiveness between ceftriaxone and sulbactam-ampicillin in the

treatment of CAP could be attributed to the anaerobic bacteria, which are common causes
of aspiration pneumonia [27]. However, anaerobic bacteria can also cause pneumonia in
patients without any apparent risk factors for aspiration pneumonia. Molecular methods
using 16S ribosomal ribonucleic acid gene sequences have yielded the bacteriological infor-
mation of CAP and demonstrated that anaerobes were detected in 17.9% of patients with
CAP [28]. As mentioned in this study, it is not clear whether anaerobic bacteria are the pri-
mary cause. In fact, the included studies did not completely report the causative pathogens.
S. pneumoniae and H. influenzae are the two most common aerobic isolates associ-
ated with CAP [29]. Ceftriaxone is superior to sulbactam-ampicillin for the treatment of
penicillin-resistant pneumococci based on the clinical efficacy and in vitro susceptibility [30].
Additionally, ceftriaxone has superior in vitro activity compared with sulbactam-ampicillin
against H. influenzae, including ampicillin-resistant strains [31]. Therefore, ceftriaxone will
likely reduce the mortality rate to a greater degree compared with sulbactam-ampicillin.
By contrast, ceftriaxone targets a narrower spectrum of anaerobes associated with CAP com-
pared with sulbactam-ampicillin [12] and has low susceptibility to Prevotella spp., which
are the primary oral anaerobes associated with CAP [32,33]. Moreover, a recent study re-
ported that β-lactamase-positive strains were detected in 80–85% of ceftriaxone-susceptible
anaerobes [34]. Therefore, considering anaerobic bacteria and β-lactamase-positive strains
as causes of CAP, sulbactam-ampicillin will more likely improve the mortality and clinical
cure rates in patients with this condition compared with ceftriaxone. In particular, it is
necessary to consider sulbactam-ampicillin in patients with an unfavorable clinical course
with ceftriaxone therapy. However, further studies are needed to associate the effectiveness
of antibiotics with CAP pathogens.
Our meta-analysis has some limitations, the most important of which is the lack of
sufficient data. In fact, retrospective studies investigating the efficacy of CAP treatment
were primarily included in this meta-analysis. Therefore, they are susceptible to bias and
confounding factors. However, a prospective study was included in this study. Moreover,
more in-depth analyses were precluded, as individual patient data were not available.
Finally, the bacteriological origin of CAP was not identified in detail. Therefore, further
well-designed studies are required to confirm our findings.

4. Materials and Methods

4.1. Study Design, Data Sources, and Search Strategy
This study was conducted according to the Preferred Reporting Items for Systematic
Review and Meta-Analysis guidelines on reporting systematic reviews and meta-analyses
(Figure S1) [35,36]. The following population, intervention, comparison, and outcomes
criteria were used for study selection: population (P), patients with CAP; intervention
(I), patients treated with ceftriaxone; comparison (C), patients treated with sulbactam-
ampicillin; and outcome (O), overall mortality and clinical cure rate. The Embase, Scopus,
PubMed, Ichushi, and Cumulative Index to Nursing and Allied Health Literature databases
were searched from inception to 26 July 2022 using a combination of the following terms:
“pneumonia,” “ceftriaxone,” and “ampicillin sulbactam.” If the original article did not
include enough information about the outcomes, we requested additional data from the
corresponding authors through e-mail. Only articles published in either English or Japanese
were included.

4.2. Study Selection

Two reviewers (HK and MH) independently screened the publications based on the
titles and abstracts, and subsequently evaluated the full text of the candidate articles.
The articles were reviewed based on the inclusion and exclusion criteria, and studies were
identified for final qualitative synthesis and meta-analysis. If the original article did not
include sufficient information about the outcomes, additional data were requested from
Antibiotics 2022, 11, 1291 6 of 8

the corresponding authors through email. One author (HM) resolved any disagreement
between the two primary reviewers [37].

4.3. Eligibility Criteria

Studies that met the following criteria were extracted: (i) RCTs and retrospective obser-
vational and cohort studies, (ii) studies conducted on patients diagnosed with pneumonia,
and (iii) studies conducted on patients receiving ceftriaxone or sulbactam-ampicillin as an
initial treatment. Studies that included patients with lung abscesses were excluded.

4.4. Data Extraction and Risk of Bias Assessment

The individual study data were extracted using a standardized data extraction form.
The data included study design, setting, period and country of the study, total number of
participants, agents used along with the dosage, number of patients included, duration of
therapy, age of patients, population, and isolated pathogens. The primary outcome was
all-cause mortality. The secondary outcome was clinical cure, which was defined as the
resolution of baseline clinical signs and symptoms of pneumonia with improvement of
the patient’s condition [38]. The risk of bias was assessed independently by two reviewers
(HK and MH) using the RoBANS tool [39]. The criteria for assessing the risk of bias were
selection of participants, confounding variables, measurement of exposure, blinding of
outcome assessment, incomplete outcome data, and selective outcome reporting.

4.5. Data Synthesis and Analysis

A standard meta-analysis was performed using Review Manager (RevMan, version 5.4;
Cochrane Collaboration, Oxford, United Kingdom). The statistical heterogeneity between
studies was evaluated using a chi-square test. Heterogeneity was defined as significant
when the p value was <0.1 or the I2 value was >50%. Fixed and random effects models
were applied when the data were considered homogenous and heterogeneous, respectively.
The risk was calculated using ORs and 95% CIs. The pooled ORs and 95% CIs were
calculated using a fixed- or random-effects model, and the ORs from these results were
compared [37].

5. Conclusions
In conclusion, the present study revealed that ceftriaxone was comparable to sulbactam-
ampicillin as an initial treatment of CAP in terms of clinical effectiveness. Therefore, our
results support guidelines for the treatment of CAP, although more RCT studies are needed
to obtain a deeper understanding.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/antibiotics11101291/s1, Figure S1: PRISMA 2020 Checklist.
Refs. [40,41] are cited in Supplementary Materials.
Author Contributions: Conceptualization, H.K. and H.M.; methodology, H.K. and M.H.; software,
H.K.; validation, N.A. and J.H.; formal analysis, H.K. and M.H.; investigation, H.K. and M.H.;
resources, H.K. and N.A.; data curation, H.K. and N.A.; writing—original draft preparation, H.K.;
writing—review and editing, M.H., N.A., J.H., Y.Y., T.I. and H.M.; visualization, H.K. and M.H.;
supervision, H.M.; project administration, H.K.; funding acquisition, H.M. All authors have read and
agreed to the published version of the manuscript.
Funding: The work was supported by JSPS KAKENHI (Grant No. 22K15318).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data are applicable in the paper.
Conflicts of Interest: The authors declare that they have no conflict of interest.
Antibiotics 2022, 11, 1291 7 of 8

References
1. Torres, A.; Peetermans, W.E.; Viegi, G.; Blasi, F. Risk factors for community-acquired pneumonia in adults in Europe: A literature
review. Thorax 2013, 10, 1136. [CrossRef] [PubMed]
2. McLaughlin, J.M.; Johnson, M.H.; Kagan, S.A.; Baer, S.L. Clinical and economic burden of community-acquired pneumonia in the
Veterans Health Administration, 2011: A retrospective cohort study. Infection 2015, 10, 1007. [CrossRef] [PubMed]
3. Tichopad, A.; Roberts, C.; Gembula, I.; Hajek, P.; Skocynska, A.; Hryniewicz, W.; Jahnz-Rozyk, K.; Prymula, R.; Solovic, I.; Kolek,
V. Clinical and economic burden of community-acquired pneumonia among adults in the Czech Republic, Hungary, Poland and
Slovakia. PLoS ONE 2013, 10, e71375. [CrossRef] [PubMed]
4. Center for Disease Control and Prevention. NAMCS/NHAMCS-About the Ambulatory Health Care Surveys; Center for Disease
Control and Prevention: Atlanta, GA, USA, 2017.
5. Brown, J.D.; Harnett, J.; Chambers, R.; Sato, R. The relative burden of community-acquired pneumonia hospitalizations in older
adults: A retrospective observational study in the United States. BMC Geriatr. 2018, 10, 1186. [CrossRef]
6. Ho, J.; Ip, M. Antibiotic-resistant community-acquired bacterial pneumonia. Infect. Dis. Clin. N. Am. 2019, 33, 1087–1103.
[CrossRef]
7. Cao, B.; Qu, J.X.; Yin, Y.D.; Eldere, J.V. Overview of antimicrobial options for Mycoplasma pneumoniae pneumonia: Focus on
macrolide resistance. Clin. Respir. J. 2017, 11, 419–429. [CrossRef]
8. Ishida, T.; Hashimoto, T.; Arita, M.; Tojo, Y.; Tachibana, H.; Jinnai, M. A 3-year prospective study of a urinary antigen-detection
test for Streptococcus pneumoniae in community-acquired pneumonia: Utility and clinical impact on the reported etiology.
J. Infect. Chemother. 2004, 10, 359–363. [CrossRef]
9. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-
acquired, ventilator-associated, and healthcare-associated pneumonia. Am. J. Respir. Crit. Care Med. 2005, 171, 388–416.
[CrossRef]
10. Barlett, J.G.; Dowell, S.F.; Mandell, L.A.; File, T.M., Jr.; Musher, D.M.; Fine, M.J. Practice guidelines for the management of
community-acquired pneumonia in adults. Clin. Infect. Dis. 2000, 31, 347–382. [CrossRef]
11. Schaberg, T.; Torres, A. Guidelines for management of adult community-acquired lower respiratory tract infections. Eur. Respir. J.
1998, 11, 986–991.
12. Finegold, S.M. Aspiration pneumonia. Rev. Infect. Dis. 1991, 13, S737–S742. [CrossRef] [PubMed]
13. Bartlett, J.G. How important are anaerobic bacteria in aspiration pneumonia: When should they be treated and what is optimal
therapy. Infect. Dis. Clin. N. Am. 2013, 27, 149–155. [CrossRef] [PubMed]
14. Citron, D.M.; Tyrrell, K.L.; Merriam, C.V.; Goldstein, E.J. In Vitro activity of ceftaroline against 623 diverse strains of anaerobic
bacteria. Antimicrob. Agents Chemother. 2010, 54, 1627–1632. [CrossRef] [PubMed]
15. Lupisan, S.; Suzuki, A.; Macalalad, N.; Egos, R.; Sombrero, L.; Okamoto, M.; Dapat, C.; Mondoy, M.; Galang, H.; Zeta, V.; et al.
Etiology and epidemiology of community-acquired pneumonia in adults requiring hospital admission: A prospective study in
rural Central Philippines. Int. J. Infect. Dis. 2019, 80, 46–53. [CrossRef] [PubMed]
16. Farahat, F.; Bukhari, O.; Basfar, I.; Alammari, A.; Zaatari, A.; Alsaedi, A.; Alshamrani, M. Clinical characteristics and outcomes of
community-acquired pneumonia in western Saudi Arabia: A four-year retrospective analysis of medical records. J. Infect. Public
Health 2021, 14, 960–966. [CrossRef]
17. Pichichero, M.E.; Casey, J.R. Safe use of selected cephalosporins in penicillin-allergic patients: A meta-analysis. Otolaryngol. Head
Neck Surg. 2007, 136, 340–347. [CrossRef]
18. Bai, F.; Li, X. Comparing several treatments with antibiotics for community-acquired pneumonia: A systematic review and
meta-analysis of randomized controlled trials. Iran. J. Public Health 2021, 50, 1108–1119.
19. Shinoda, Y.; Matsuoka, T.; Mori, T.; Yoshida, S.; Ohashi, K.; Yoshimura, T.; Sugiyama, T. Antibacterial therapy of aspiration
pneumonia in patients with methicillin-resistant Staphylococcus aureus-positive sputum: Identification of risk factors. Pharmazie
2016, 71, 109–112.
20. Terahara, F.; Kisa, K.; Yamada, K.; Yokokawa, Y.; Saito, S. Efficacy of ceftriaxone in aspiration pneumonia; propensity score
matched retrospective observational study, compared with sulbactam/ampicillin. Jpn. J. Pharm. Health Care Sci. 2017, 43, 306–312.
[CrossRef]
21. Hasegawa, S.; Shiraishi, A.; Yaegashi, M.; Hosokawa, N.; Morimoto, K.; Mori, T. Ceftriaxone versus ampicillin/sulbactam for the
treatment of aspiration-associated pneumonia in adults. J. Comp. Eff. Res. 2019, 8, 1275–1284. [CrossRef]
22. Hamano, N.; Ito, I.; Konishi, S.; Tanabe, N.; Shirata, M.; Oi, I.; Tsukino, M.; Matsumoto, H.; Yasutomo, Y.; Kadowaki, S.; et al.
Comparison of ceftriaxone plus macrolide and ampicillin/sulbactam plus macrolide in treatment for patients with community-
acquired pneumonia without risk factors for aspiration: An open-label, quasi-randomized, controlled trial. BMC. Pulm. Med.
2020, 20, 160.
23. Xaba, S.N.; Greeff, O.; Becker, P. Determinants, outcomes and costs of ceftriaxone v. amoxicillin-clavulanate in the treatment of
community-acquired pneumonia at Witbank hospital. S. Afr. Med. J. 2014, 104, 187–191. [PubMed]
24. Sanchez, M.E.; Vargas, J.G.; Baños, V.; Gómez, J.R.; Muñoz, L.; Simarro, E.; Soto, M.C.; Canteras, M.; Valdés, M. Prospective and
comparative study between cefuroxime, ceftriaxone and amoxicillin-clavulanic acid in the treatment of community-acquired
pneumonia. Rev. Esp. Quimioter. 1998, 11, 132–138.
25. Leishker, A.H.; Kolb, G.F. Aspiration pneumonia: Management in Germany. Eur. Geriatr. Med. 2011, 2, 184–186. [CrossRef]
Antibiotics 2022, 11, 1291 8 of 8

26. Kohno, S.; Imamura, Y.; Shindo, Y.; Seki, M.; Ishida, T.; Teramoto, S.; Kadota, J.; Tomono, K.; Watanabe, A. Clinical practice
guidelines for nursing- and healthcare-associated pneumonia (NHCAP). Respir. Investig. 2013, 51, 103–126. [CrossRef] [PubMed]
27. Tokuyasu, H.; Harada, T.; Watanabe, E.; Okazaki, R.; Touge, H.; Kawasaki, Y.; Shimizu, E. Effectiveness of meropenem for the
treatment of aspiration pneumonia in elderly patients. Intern. Med. 2009, 48, 129–135. [CrossRef]
28. Akata, K.; Yatera, K.; Yamasaki, K.; Kawanami, T.; Naito, K.; Noguchi, S.; Fukuda, K.; Ishimoto, H.; Taniguchi, H.; Mukae, H.
The significance of oral streptococci in patients with pneumonia with risk factors for aspiration: The bacterial floral analysis of
16S ribosomal RNA gene using bronchoalveolar lavage fluid. BMC. Pulm. Med. 2016, 16, 79. [CrossRef]
29. Taylor, J.K.; Fleming, G.B.; Singanayagam, A.; Hill, A.T.; Chalmers, J.D. Risk factors for aspiration in community-acquired
pneumonia: Analysis of a hospitalized UK cohort. Am. J. Med. 2013, 126, 995–1001. [CrossRef]
30. Heffelfinger, J.D.; Dowell, S.F.; Jorgensen, J.H.; Klugman, K.P.; Mabry, L.R.; Musher, D.M.; Plouffe, J.F.; Rakowsky, A.; Schuchat,
A.; Whitney, C.G. Management of community-acquired pneumonia in the era of pneumococcal resistance: A report from the
drug-resistant Streptococcus pneumoniae therapeutic working group. Arch. Intern. Med. 2000, 160, 1399–1408. [CrossRef]
31. Ohno, A.; Ishii, Y.; Kobayashi, I.; Yamaguchi, K. Antibacterial activity and PK/PD of ceftriaxone against penicillin-resistant
Streptococcus pneumoniae and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae isolates from patients with
community-acquired pneumonia. J. Infect. Chemother. 2007, 13, 296–301. [CrossRef]
32. Bartlett, J.G. Anaerobic bacterial infection of the lung. Anaerobe 2012, 18, 235–239. [CrossRef] [PubMed]
33. Dubreuil, L.; Behra-Miellet, J.; Vouillot, C.; Bland, S.; Sedallian, A.; Mory, F. β-lactamase production in Prevotella and in vitro
susceptibilities to selected β-lactam antibiotics. Int. J. Antimicrob. Agents 2003, 21, 267–273. [CrossRef]
34. Fujita, K.; Takata, I.; Sugiyama, H.; Suematsu, H.; Yamagishi, Y.; Mikamo, H. Antimicrobial susceptibilities of clinical isolates of
the anaerobic bacteria which can cause aspiration pneumonia. Anaerobe 2019, 57, 86–89. [CrossRef]
35. The Guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement. Available online:
http://prisma-statement.org (accessed on 29 August 2022).
36. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and
me-ta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [CrossRef] [PubMed]
37. Kato, H.; Hagihara, M.; Asai, N.; Hirai, J.; Yamagishi, Y.; Iwamoto, T.; Mikamo, H. A systematic review and meta-analysis of
efficacy and safety of azithromycin versus moxifloxacin for the initial treatment of Mycoplasma genitalium. Antibiotics 2022,
11, 353. [CrossRef]
38. Kato, H.; Hagihara, M.; Morikawa, Y.; Asai, N.; Mikamo, H.; Iwamoto, T. Retrospective comparison of the effectiveness and safety
of ceftriaxone 1 g twice daily versus 2 g once daily for treatment of aspiration pneumonia. Antibiotics 2022, 11, 983. [CrossRef]
39. Kim, S.Y.; Park, J.E.; Lee, Y.J.; Seo, H.J.; Sheen, S.S.; Hahn, S.; Jang, B.H.; Son, H.J. Testing a tool for assessing the risk of bias for
nonrandomized studies showed moderate reliability and promising validity. J. Clin. Epidemiol. 2013, 66, 408–414. [CrossRef]
40. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.;
Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71.
[CrossRef]
41. Available online: http://www.prisma-statement.org/ (accessed on 19 September 2022).