Ceftriaxone combination therapy versus respiratory fluoroquinolone monotherapy for community-acquired pneumonia: A meta-analysis

a b s t r a c t

Background: The goal of this study was to investigate whether ceftriaxone Combination therapy is associated with better clinical outcomes than respiratory fluoroquinolone monotherapy for adults with community-acquired pneumonia . We conducted a meta-analysis of published studies.

Methods: Using the PubMed, EMBASE, and Cochrane Library databases, we performed a literature search of avail- able Randomized controlled trials published as original articles before September 2017.

Results: Nine RCTs, involving 1520 patients, were included in the meta-analysis. The pooled Relative risks (RRs) for the efficacy of ceftriaxone combination therapy versus respiratory fluoroquinolones monotherapy were

0.96 (95% CI: 0.92-1.01), based on clinically evaluable populations, and 0.93 (95% CI: 0.88-0.99) based on inten-

tion-to-treat (ITT) populations. No statistically significant differences were observed in microbiological treat- ment success (pooled RR = 0.99, 95% CI: 0.90-1.09), although drug-related adverse events were significantly lower with ceftriaxone combination therapy than with respiratory fluoroquinolones monotherapy (pooled RR

= 1.27, 95% CI: 1.04-1.55).

Conclusions: Current evidence showed that the efficacy of ceftriaxone combination therapy was similar to respi- ratory fluoroquinolone monotherapy for hospitalized CAP patients, and was associated with lower drug-related adverse events.

Introduction

Community-acquired pneumonia is one of the leading causes of death and hospitalization for all age groups throughout the world [1,2]. Short-term mortality (in-hospital and 30-day mortality) for hospi- talized patients with CAP ranges from 4.0% to 18.0% [3]. It is likewise the most frequent cause of Community-acquired infections admitted to in- tensive care units (ICU) [4], and mortality can reach 50% for patients in the ICU [5]. The most common cause of CAP is Streptococcus pneumoniae [6-8]. However, it is a challenge to treat CAP due to in- creased incidence of antibiotic resistance [9,10] and the occurrence of other atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella species). The treatment of CAP requires anti- biotics, and inappropriate use of them in the community and hospitals has contributed to resistance. Thus, antibiotic therapy for CAP should be focused on the most efficient and effective antibiotic regimens.

Patients’ outcomes from CAP depend on Timely diagnosis and treat-

ment, involving appropriate antimicrobial therapy directed at the most common possible Respiratory pathogens. Beta-lactam-based therapy for

* Corresponding author at: Department of Emergency Medicine, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, China.

E-mail address: [email protected] (Y.-Q. Zhang).

CAP covers the most common possible pathogens involved in the path- ogenesis of CAP and acts as one of the first-line standard treatments. It was suggested that patients be administered third-generation cephalo- sporin, such as cefotaxime or ceftriaxone, for high-severity CAP [11]. Ceftriaxone is a broad-spectrum antibiotic, most commonly used in the emergency department, particularly for patients with community- acquired pneumonia [12]. Fluoroquinolones have also been considered a possible regimen for CAP because of their effectiveness as a single agent [13], low spontaneous mutation rate for resistance, and cost-sav- ing potential [14]. However, previous studies were not consistent and did not assess which was the better choice for CAP. We aimed to com- pare the efficacy, drug-related adverse events, and microbiological re- sponses to ceftriaxone combination therapy with respiratory fluoroquinolone monotherapy for the treatment of CAP and conducted a meta-analysis of randomized controlled trials.

Methods

Search strategy

A systematic search was performed in the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (Cochrane Library Issue 1 of 9, 2017) databases to find studies published before September

https://doi.org/10.1016/j.ajem.2018.01.079

treatment success“>2017. Because several quinolones have been withdrawn from clinical use since the conduct of the trials, we used the keywords “levofloxacin”, “moxifloxacin”, “ceftriaxone” in combination with “community ac- quired pneumonia” and “CAP” to search the literature. There was no limitation on language or date of publication. We reviewed the refer- ence lists of included articles for additional studies.

Selection criteria

Studies were included in the meta-analysis if they fulfilled the fol- lowing criteria: (1) Randomized controlled trials of adults aged N18 years with community acquired pneumonia (CAP); (2) comparison of the clinical efficacy and/or safety of ceftriaxone combination therapy versus respiratory fluoroquinolones monotherapy; (3) trials with blinded or unblinded design were included.

Data extraction and risk of bias

Data on study characteristics, treatment success, microbiological treatment success, and drug-related adverse events (AEs) were ab- stracted onto a standardized form by 2 authors independently and dis- crepancies were resolved by consensus in consultation with a third reviewer. The risk of bias for included studies was assessed by the Cochrane Collaboration’s tool for evaluating study bias [15].

Analyzed outcomes

Treatment success was defined as primary outcome at the test-of- cure (TOC) visit based on clinically evaluable and ITT populations. The secondary outcomes included drug-related adverse events (AEs) and microbiological treatment success. Treatment success was defined as “clinical cure”, which was the disappearance of all signs and symptoms related to infection.

Statistical analysis

The statistical heterogeneity among studies was tested with the Q statistic, and inconsistency was quantified with the I² statistic [16]. For the Q statistic, statistical significance was set at P b 0.1. When heteroge- neity was detected, the random-effects model was used [17]. Analyses were performed with STATA 14.0 (StataCorp, College Station, TX, USA) and RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark).

Results

Study characteristics and risk of bias

Six hundred sixty-eight potentially relevant articles were identified using the pre-defined search criteria by a primary computerized litera- ture search. After screening titles and abstracts and reviewing the full- text articles, nine RCTs [18-27] were included (Fig. 1). Of these studies, six were in English, two were in Chinese, and one was in Spanish. The majority of participants included in the studies were the patients with moderate and/or severe CAP. The length of treatment was 7-14 days in most studies. The main characteristics of the studies that were in- cluded in the meta-analysis are summarized in Tables 1. The risk of bias summary for included studies is listed in Fig. 2.

Treatment success

All included trials reported the treatment success for clinically evaluable populations at the test-of-cure (TOC) visit. In Fig. 3, the anal- ysis of all the studies revealed that there was no difference in treatment success between ceftriaxone combination therapy and respiratory fluo- roquinolone monotherapy (pooled RR = 0.96, 95% CI: 0.92-1.01) based on clinically evaluable populations. Only five trials provided data about

treatment success for ITT populations at the TOC visit. Ceftriaxone com- bination therapy was slightly more effective than respiratory fluoro- quinolone monotherapy (pooled RR = 0.93, 95% CI: 0.88-0.99) based on ITT populations, as shown in Fig. 4.

Drug-related adverse effects

Data on drug-related AEs in the clinically evaluable populations were reported for six trials. The most common AEs were gastrointestinal disturbances, including diarrhea, vomiting, and other GI complaints. Fig. 5 shows that ceftriaxone combination therapy was associated with fewer adverse events (pooled RR = 1.27, 95% CI: 1.04-1.55).

Microbiological treatment success

Four of the nine relevant RCTs provided microbiological treatment success outcomes. No significant difference was observed between a ceftriaxone combination regimen and respiratory fluoroquinolone monotherapy (pooled RR = 0.99, 95% CI: 0.90-1.09), as shown in Fig. 6.

Discussion

To our knowledge, no meta-analysis comparing respiratory fluoro- quinolone monotherapy to ceftriaxone combination therapy for com- munity-acquired pneumonia has been published. A total of 1520 patients in 9 independent studies were identified in this meta-analysis. The results of this meta-analysis indicated that ceftriaxone combination therapy was similar to respiratory fluoroquinolone monotherapy, and the drug-related AEs were fewer in the ceftriaxone combination therapy regimen.

A meta-analysis conducted by Vardakas et al. [28] reported that re- spiratory fluoroquinolones were associated with higher clinical efficacy than combination therapy was. Similarly, a cohort from Querol-Ribelles JM et al. [29] also reported that levofloxacin was superior to the combi- nation of ceftriaxone and clarithromycin in the treatment of commu- nity-acquired pneumonia that requires hospitalization. Furthermore, Fan H et al. [30] reported that in the treatment success rates, no signifi- cant differences were found between the respiratory fluoroquinolone monotherapy and the ?-lactams plus macrolides combination therapy based on the data of intention-to-treat (ITT) and per-protocol (PP) anal- yses. Our meta-analysis demonstrated that the efficacy of ceftriaxone combination therapy was similar to respiratory fluoroquinolone mono- therapy for hospitalized CAP patients, with higher treatment success rates based on ITT populations.

In the included studies, in which drug-related adverse events were mentioned, the most common AEs for ceftriaxone were gastrointestinal disorders, such as diarrhea and vomiting; other AEs were phlebitis, nau- sea, rash, and so on. Macrolides were the most common combination drug regimen with ceftriaxone; six studies (azithromycin in three arti- cles, clarithromycin in two articles, and erythromycin in two articles) used it. It was reported that Clostridium difficile infection, enterocolitis, central nervous system (CNS) effects, and digestive effects are common drug-related AEs in patients taking macrolide antibiotics [31]. For the compared regimens, fluoroquinolones can cause a range of serious drug-related adverse events. The drug-related adverse events that were reported in the included studies were gastrointestinal disorder (nausea, vomiting, diarrhea), rash, urticarial, phlebitis, dizziness, insom- nia, paroniria, seizures, and headache. In addition, the Food and Drug Administration recently advised restricting fluoroquinolone anti- biotic use for its potential side effects [32]. All in all, there were fewer drug-related adverse events in CAP patients taking ceftriaxone combi- nation therapy in our meta-analysis, which may make it a better choice for treating CAP.

The results of this meta-analysis indicated that there was no statisti- cal difference between the two antibiotic regimens in microbiological treatment success. However, another meta-analysis reported that

Fig. 1. Flow diagram of meta-analysis literature search results.

Table 1

Characteristics of the included studies.

Study	Year	Type of study	Included population	Drug regimens		Enrolled	Intention
				Ceftriaxone combination	Respiratory quinolone	population	to treat
					monotherapy
Frank	2002	Multicenter, randomized,	Patients >=18 years old with a	i.v. azithromycin 0.5 g OD + i.v.	i.v./p.o.levofloxacin 0.5 g	236	121 vs.
		open-label study	primary diagnosis of CAP	ceftriaxone 1 g OD	OD		115
Erard	2004	Randomized, open-label,	Patients >=18 years old admitted	i.v. ceftriaxone 2 g OD +- i.v./p.o.	p.o. levofloxacin 1 g OD	129	37 vs. 79
		controlled pilot	for the treatment of CAP	clarithromycin 1 g OD
		observational study
Fogarty	2004	Randomized, open-label,	Patients >=18 years old with signs	i.v/i.m. ceftriaxone sodium 1-2g	p.o. levofloxacin 1 g OD	269	137 vs.
		comparative, study	and symptoms of CAP	OD + i.v. erythromycin 0.5-1			132
				g/6 h
Zervos	2004	Multicenter randomized,	Patients >=18 years old with a	i.v. ceftriaxone 1 g OD + i.v.	i.v. levofloxacin 0.5 g OD	219	112 vs.
		open-label study	clinical diagnosis of CAP	azithromycin 0.5 g OD			107
Welte	2005	Multicenter, randomized,	Patients >=18 years old with a	i.v. ceftriaxone 2 g OD +- i.v.	i.v. moxifloxacin 0.4 g OD	397	197 vs.
		controlled, nonblinded study	primary diagnosis of CAP	erythromycin 1 g OD			200
Yang	2009	Randomized study	Elderly patients with moderate to	i.v. ceftriaxone sodium 2 g OD+	i.v. moxifloxacin	100	50 vs. 50
			severe CAP	i.v. azithromycin 0.5 g OD	hydrochloride sodium
					chloride 0.4 g OD
Liu	2010	Randomized, controlled	Patients >=18 years old with a	i.v. ceftriaxone sodium 2 g OD +	i.v. moxifloxacin sodium	58	30 vs. 28
		clinical study	primary diagnosis of CAP	i.v. azithromycin 0.5 g OD	chloride OD
Lee	2012	Randomized, open-label	Patients admitted to a hospital for	i.v. ceftriaxone 2 g OD + p.o.	i.v. levofloxacin 0.75 g OD	40	20 vs. 20
		study	CAP treatment	azithromycin 0.5 g OD
Lopez-Vejar	2013	Randomized, open-label,	Patients >=18 years old with CAP	i.v. ceftriaxone 2 g b.i.d. + p.o.	i.v/p.o. levofloxacin 0.75 g	72	36 vs. 36
		controlled study	with a severity index of	clarithromycin 0.5 g b.i.d.	OD
			pneumonia >= III

i.v.: intravenous, OD: once daily, b.i.d.: twice daily, p.o.: oral.

Fig. 2. Risk of bias graph and summary.

moxifloxacin had a favorable microbiological treatment success rate compared with ?-lactam-based regimens [14]. It seemed that for micro- biological treatment success, ceftriaxone combination therapy was not superior to respiratory fluoroquinolones monotherapy.

Several potential limitations of this meta-analysis should be noted. First, the included studies in this meta-analysis were open-label trials. Consequently, the relatively low quality of the included trials may affect our findings. Second, our meta-analysis was based on a small number of studies, and the results in this paper may also be affected. Third, one RCT

[25] assessed the efficacy and safety in the elderly and one RCT [24] in- cluded only patients with mycoplasma pneumonia, making these re- sults also less applicable to the general population.

The findings of this meta-analysis suggest that ceftriaxone combina- tion therapy was as efficacious as respiratory fluoroquinolones

monotherapy, but the drug-related AEs were lower in the ceftriaxone combination therapy regimen. Given the limitation of quantity and quality of these included studies, more high-quality RCTs are required to explore the conclusion further.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

This work was supported by grants from the Medical Science Re- search Program of the Health and Family Planning Commission [Grant number 20160210] and Provincial Science and Technology Social

Fig. 3. Forest plots of treatment success, comparing respiratory ceftriaxone combination therapy with fluoroquinolone monotherapy for the treatment of CAP, based on the clinically evaluable population.

Fig. 4. Forest plots of treatment success, comparing respiratory ceftriaxone combination therapy with fluoroquinolones monotherapy for the treatment of CAP, based on the ITT population.

Fig. 5. Forest plots of drug-related adverse effects comparing ceftriaxone combination therapy with respiratory fluoroquinolone monotherapy.

Fig. 6. Forest plots of microbiological treatment success comparing ceftriaxone combination therapy with respiratory fluoroquinolone monotherapy.

Benefit Program [Grant number 15277710D] in Hebei Province. The funders had no role in study design, data collection and analysis, deci- sion to publish, or preparation of the manuscript.

References

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