Community-acquired respiratory tract infections (RTIs), such as the most common diseases in many countries, may lead to significant morbidity and mortality if not managed effectively. In 1996, RTIs accounted for 16% of all outpatient visits in the USA, and were responsible for 99 days lost from work per 100 employed individuals,1
this illustrates that community-acquired RTIs are associated with an appreciable socioeconomic burden.2-4Acute bacterial exacerbations of chronic bronchitis (ABECB), community-acquired pneumonia (CAP), and tonsillitis/pharyngitis are 3 common RTIs in adults that pose a significant treatment challenge for clinicians in the primary care setting.2-4
Although many RTIs are caused by viruses, a substantial proportion of these infections are still bacterial in nature. Once a bacterial infection is suspected, it is important to initiate treatment with antibiotics promptly. Antibiotic therapy based on clinical and radiologic diagnosis is often empirical, targeting the most common causative pathogens. A suitable empiric regimen needs to consider the important organisms that most commonly underlie the pathogenesis of RTIs, includingStreptococcus pneumoniae,Haemophilus influenzae,Moraxella catarrhalisandStreptococcus pyogenes, as well as atypical respiratory pathogens such asChlamydophilaandMycoplasma.3-5Traditionally, oral β-lactams have formed the mainstay of initial empiric therapy for RTIs in the outpatient setting. However, these agents have now been largely superseded in this regard by the newer macrolides, such as clarithromycin and azithromycin, because of a greater appreciation of the importance of certain gram-negative and atypical pathogens. However, with the widespread consumption of macrolides, increasing proportions of respiratory pathogens, especiallyS. pneumoniae, are becoming resistantto these antibiotics.6
Although there is significant geographical variation, the overall prevalence ofS. pneumoniaestrains resistant to clarithromycin has been reported to be approximately 30%, similar to that found for penicillin G and erythromycin A (22% and 31%).8
This emerging situation suggests an urgent need for agents that are active against common respiratory pathogens, including resistant organisms.
Telithromycin, a ketolide antibacterial that is structurally related to macrolides, has been developed specifically to provide optimal therapy for the treatment of RTIs caused by either typical or atypical respiratory pathogens. Importantly, telithromycin shows potentin vitroactivity againstS. pneumoniae, including strains that are resistant to penicillin and/or macrolides.9-11Several randomized controlled trials (RCTs) have been carried out to compare the efficacy and safety of telithromycin with that of clarithromycin. This paper presents a systematic review with a meta-analysis of the relevant RCTs12-16to establish whether telithromycin may be a suitable alternative to clarithromycin for the management of RTIs in adults.
An extensive search of the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2012), PubMed (1980 to Sep. 2012), Embase (1980 to Sep. 2012), CNKI (1980 to Sep. 2012) and VIP (1980 to Sep. 2012) databases was carried out to identify relevant RCTs for our meta-analysis. Search terms included “telithromycin”, “clarithromycin”, “community-acquired respiratory tract infections” and similar, “community-acquired pneumonia” and similar, “acute exacerbations of chronic bronchitis” and similar, “tonsillitis/pharyngitis” and similar, and “acute bacterial sinusitis” and similar. References from relevant articles, including review papers, were also examined. The RCTs that were not available to us were requested from the authors.
Two reviewers (HS and MMA) independently searched the literature and examined relevant RCTs for further assessment. A study was included in our meta-analysis if it fulfilled the following including criteria: (1) RCT; (2) involving patients of any age with RTIs such as CAP, ABECB, tonsillitis/pharyngitis, etc.; (3) Comparing treatment with telithromycin against clarithromycin; (4) including specific data regarding clinical treatment success, microbiological treatment success, and adverse effects; (5) Trials with or without blinded design were considered acceptable. Abstracts in scientific conferences were not included in the meta-analysis. The excluding criteria were: (1) non-RCT; (2) experimental trials and studies focusing on pharmacokinetic or pharmacodynamic variables.
Evaluation of the methodological quality of each RCT included in the meta-analysis was performed independently by two reviewers (Sun SG and Zhang WD) using the Jadad scoring system.17-19
Two reviewers (Sun SG and Zhang WD) independently extracted data from each included trial, with the aid of a predesigned review form. In case of any disagreement between the two reviewers, a third reviewer extracted the data and results were attained by consensus. We contacted the authors of trials for missing information when necessary.
The following data were extracted from each study: year of publication, clinical setting, patient population, number of patients (intention to treat (ITT), modified intention to treat (MITT), and per-protocol (PP) populations), antimicrobial agents and doses used, clinical and microbiological treatment outcomes, treatment emergent adverse effects (TEAEs), and drug-related adverse effects (DRAEs). The MITT population was composed of randomized patients who received at least one dose of study drug and met the minimal disease definition. The PP population comprised patients that fulfilled all inclusion and exclusion criteria in the individual RCTs, had complete follow-up, and for whom data on treatment outcomes were available but not indeterminate.
Definitions of infections
Infections were defined according to the definitions used by the individual RCTs. Definitions of infections did not differ substantially between the RCTs included in the meta-analysis.
CAP was defined as those cases with a chest X-ray finding indicative of bacterial pneumonia, combined with the onset of two or more of the following signs and symptoms: cough, production of purulent sputum, auscultatory findings, dyspnea or tachypnea. In addition, patients were required to have at least one of the following: fever (oral temperature >38°C; tympanic temperature >38.5°C; rectal temperature >39°C), an elevated total white blood cell (WBC) count, or a Gram stain on a respiratory sample showing gram-positive diplococci. Patients with ABECB were defined on the basis of having a history of chronic bronchitis or chronic obstructive pulmonary disease (COPD), and presentation with one or more of the following symptoms and signs: increased dyspnea, increased sputum volume, increased sputum purulence, and presumption of bacterial infection. Tonsillitis/pharyngitis was defined as an illness with a sore throat and one or more of the following signs: fever, erythema or edema of the posterior pharynx, pharyngeal exudates, or cervical lymphadenopathy.
The primary efficacy outcome of this meta-analysis was clinical treatment success (defined as complete resolution or substantial improvement of symptoms and signs of CAP, ABECB or tonsillitis/pharyngitis, or no further antimicrobial therapy for infection was necessary) assessed at the test-of-cure (TOC) time point employed in each individual study. The secondary efficacy outcome was either clinical treatment success assessed at a late post-therapy time, or microbiological treatment success (defined as the eradication of baseline pathogens, or presumed eradication based on the clinical outcome at TOC and late-post therapy time) in the PP population for which bacteriological assessment was made. The clinical treatment success outcomes were analyzed in the PP and MITT populations of each included RCT.
The primary safety outcome of the meta-analysis was DRAEs (defined as any adverse effects which were deemed to be drug related, and were observed during the treatment and post-treatment period). The secondary safety outcome of the meta-analysis was TEAEs (defined as any adverse effects which were deemed to be treatment emergent adverse effects, and were observed during the treatment and post-treatment period).
Data analysis and statistical methods
Statistical analysis was carried out using Review Manager Version 5.0.17 software (Cochrane Collaboration, UK). We assessed heterogeneity of trial results by calculating a chi-square test of heterogeneity, withI2
used as a measure of inconsistency. Publication bias was assessed by examination of the funnel plot. Fixed-effect model (FEM) and the Mantel-Haenszel method was used for pooling odds ratios (ORs) and 95% confidence intervals (CI) for all primary and secondary outcomes (including ITT, MITT, PP and PPb populations), throughout the meta-analysis unless statistically significant heterogeneity was found (P<0.10 orI2
>50%), in which case we chose a random-effects model (REM) and used the DerSimonian and Laird method.
Figure 1 showed a flow diagram that details the screening and selection process for the trials included in this meta-analysis. The search was performed using PubMed, the Cochrane Central Register of Controlled Trials, Embase, CNKI and VIP databases. We obtained 19 full papers from 227 studies for detailed evaluation. From these, we identified 7 RCTs that fulfilled the criteria for inclusion in the meta-analysis.
The main characteristics of the 7 included RCTs (type of study design, Jadad score, characteristics of the included population, drugs tested,additional antibiotics allowed, number of enrolled patients and intention-to-treat patients) are presented in Table 1
Six trials included in the meta-analysis were carried out in adult patients with CAP or AECB (only one 15-year-old adolescent enrolled); the remaining trial was undertaken in adolescent or adult patients with acute tonsillitis/pharyngitis. All of the included studies were methodologically well performed, with double blinding protocols. High Jadad scores (2 RCTs had a score of 5, 5 had a score of 4) were alsoindicative of the high quality of the RCTs. We examined the funnel plot (SE of log OR plotted against OR) to estimate publication bias, and this showed a symmetric inverse funnel distribution.
Definitions of clinical efficacy and safety endpoints were comparable between the trials. The patients enrolled in the included trials received either telithromycin 800 mg orally once daily for 5 days,12,13,15,167 days13
or 10 days,14
or the recommended course of clarithromycin for treatment of the RTI (500 or 1000 mg daily, given as one or two doses, for 5 or 10 days). Other antibiotics were not permitted during the period of therapy with the test drug. We analyzed the outcomes at the timing of the TOC, which varied between studies with a minimum value of 3 days to a maximum value of 14 days, and at the late post-therapy time, which varied from 21 days to 35 days after completion of the study treatments.
Clinical treatment success
Extracted data regarding the primary outcome of the meta-analysis (clinical treatment success) are presented in Figure 2 and 3. Data concerning clinical treatment success for patients with community-acquired RTIs were provided in all 5 relevant RCTs. At the TOC time point, no difference was found regarding clinical treatment success between the PP population receiving telithromycin or clarithromycin (OR: 0.97, 95%CI: 0.82–1.14; Figure 2
). The similarity between results was confirmed in our conservative MITT analysis, in which patients with inadequate information or indeterminate outcomes were considered to be cases of treatment failure (OR: 0.84, 95%CI: 0.64–1.11, Figure 3
Microbiological treatment success
Figure 4 and 5 showed the secondary outcome of the meta-analysis (microbiological treatment success). Four RCTs provided information regarding microbiological treatment success. There was no difference in microbiological treatment success at a late post-therapy visit (OR: 0.92, 95%CI: 0.57–1.48, Figure 4
), and no significant difference was found in microbiological treatment success at the test-of-cure time (OR: 1.14, 95%CI: 0.71–1.85, Figure 5
Successful eradication of the key bacterial respiratory pathogens in the PPb population was excellent for both the telithromycin and clarithromycin treatment arms. We analyzed the bacteriologic eradication rates for three key bacterial respiratory pathogens (S. pneumoniae,H. influenzae,M. catarrhalis) in 4 RCTs (1 RCT was excluded, that studied patients with tonsillitis/pharyngitis in which the major pathogens were group A beta-hemolytic streptococci). As shown in Table 2, in the PPb population, treatment with telithromycin was associated with similar bacteriologic eradication rates to therapy with clarithromycin. For telithromycin, eradication rates forS. pneumoniae,H. influenza, andM. catarrhaliswere 92.4%, 84.5% and 91.3%; for clarithromycin, the respective values were 92.5%, 88.2% and 95.5%.
All 5 relevant RCTs provided information concerning DRAEs and TEAEs (Figures 6 and 7). The main adverse effects assessed by the investigators were gastrointestinal in nature, such as diarrhea, nausea, vomiting, flatulence, dyspepsia, and abdominal pain; other reported adverse effects included headache, oral candidiasis, dizziness, dysgeusia, abnormal liver function tests and fatigue. However, some patients experiments serious adverse events such as allergic reaction (chest pain, shortness of breath, throat swelling and rash), liver function abnormalities by telithromycin treatment. In Tellier et al13
studies, 3 patients died in telithromycin group and 2 died in clarithromycin due to adverse events.
The safety outcome analysis indicated telithromycin had a similar risk of treatment emergent and drug related adverse effect adverse effect with clarithromycin (OR:1.14, 95%CI: 0.85–1.54, Figure 6;OR: 1.25, 95%CI: 0.71–1.85, Figure 7
). Moreover, no significant differences were found in terms of serious adverse effect and serious adverse effect between telithromycin and clarithromycin treatment groups (OR: 0.91, 95%CI: 0.56–1.48, Figure 8
). The safety analysis suggested that telithromycin had a similar safety profile to that of clarithromycin.
The sensitivity analysis was limited to the patients that had received telithromycin for 5 days vs. clarithromycin for 10 days at the TOC time point, with the same therapy duration between the included trials. The analysis showed robust of the results. Furthermore, removal of each of the individual studies, or of studies of lower quality, did not change the overall efficacy and safety findings of this review.
This study represened the first systematic review with a meta-analysis comparing the efficacy and safety of telithromycin with that of clarithromycin, in patients with community-acquired RTIs that included CAP, ABECB and tonsillitis/pharyngitis. The main finding of thismeta-analysis is that telithromycin and clarithromycin have similar efficacy with regard to treatment of community-acquired RTIs, as determined from the primary and secondary efficacy outcomes. Furthermore, safety analyses that examined DRAEs and TEAEs suggested that telithromycin had a similar risk of adverse effect with clarithromycin.
Telithromycin, a ketolide antibacterial structurally related to the macrolides, has a spectrum of activity targeted against common pathogens that induce RTIs.9-11Macrolides have been well studied, and are approved for the treatment of RTIs such as CAP, ABECB and tonsillitis/pharyngitis.5,10,20,21
The recommended dosage of clarithromycin was chosen as the comparator treatment in our meta-analysis, since this is considered a first-line empiric therapy for RTIs. CAP, AECB and tonsillitis/pharyngitis are RTIs with similar etiologies, involving organisms that include both typical (S. pneumoniae,H. influenzae,M. catarrhalis,S. pyogenes) and atypical respiratory pathogens. Furthermore, all these RTIs are usually treated empirically with orally administered antibacterial agents, including macrolides/azalides, β-lactams, and fluoroquinolones.22-28Therefore, in our meta-analysis, we included RCTs studying patients with CAP, ABECB, or tonsillitis/pharyngitis, in order to increase the sample size and thus achieve greater statistical power.
Although the present evidence suggests that telithromycin was as effective as clarithromycin for the treatment of RTIs, and had a similar safety profile, several unique characteristics make it a useful alternative to clarithromycin. Firstly, the more widespread use of newer macrolides, such as clarithromycin, has unfortunately been paralleled by an increase in the resistance ofS. pneumoniaeto these agents, threatening to compromise
Indeed, resistance rates ofS. pneumoniaeto macrolides have been found to be as high as 30%, values similar to those reported for beta-lactams.8
In contrast, although strains resistant to telithromycin have been identified, bacterial resistance rates to this agent remain low (e.g. less than 2% forS. pneumoniae).8
The antimicrobial actions of both ketolides and macrolides are due to inhibition of bacterial protein synthesis following binding of the drug to 23S rRNA of the 50S subunit of the bacterial ribosome. The major structural modifications that differentiate telithromycin from the macrolides (replacement of the 3-cladinose residue with a 3-keto group, and addition of an 11, 12-carbamate extension) enable the drug to bind more tightly to distinct regions of rihosomal RNA.29
This dual binding not only enhances antibacterial potency but also enables the drug to overcome resistance caused by modification of one of the target sites, due to methylation.29
Telithromycin not only has a spectrum of activity targeted against common respiratory pathogens that cause RTIs, including both typical and atypical organisms, but is also effective against strains that are resistant to penicillin and/or macrolides.5
Furthermore, telithromycin also demonstrates a low potential for the selection or induction of macrolide-lincosamide-streptogramin B resistance.30
The clinical and bacteriologic efficacy of telithromycin against resistant strains of major CAP pathogens has been established in a pooled analysis of isolates from the telithromycin phase III clinical trial program, although the number of isolates was small.29
The activity of telithromycin against atypical and intracellular pathogens also has been demonstrated, both inin vitrostudies and in animal models of atypical pneumonia.10,21,32,33Secondly, treatment of RTIs with telithromycin may be associated with lower overall use of health-care resources than therapy with clarithromycin, due to reduced rates of hospitalization.34
Thirdly, the short-duration and once daily dosing of telithromycin has positive implications for increasing patient compliance and hence reducing the propensity for treatment failure.
It should be pointed out that patients with severe community-acquired RTIs (requiring admission to an intensive care unit or parenteral antibiotic therapy) were not enrolled in the RCTs we analyzed, and thus this meta-analysis was limited inscope to mild-to-moderate RTIs. It should also be noted that all the included RCTs enrolled only adolescents and adults; therefore, our study does not provide efficacy and tolerance data for telithromycin use in pediatric patients with RTIs, and its findings should therefore be interpreted with caution when considering the choice of antibiotic in children.
Our study is not without its limitations. Firstly, despite determination of efficacy outcomes by pooling results from all available properly randomized trials, our meta-analysis lacked the statistical power to provide precise estimates of the treatment effects of telithromycin on respiratory pathogens resistant to penicillin and/or macrolides, although severalin vitrostudies have demonstrated its efficacy against these resistant organisms.5,10,20,21,30,31The validity of our approach is supported by our sensitivity analysis, which showed similar efficacy and safety findings to the review overall. Thirdly, all of the 5 included trials were supported financially by the pharmaceutical company that markets and brands telithromycin; this is a factor that potentially may have generated bias in the assessment of outcomes, although all the studies included double blinding protocols.
As the meta-analysis that focuses on a direct comparison of the efficacy and safety of telithromycin and clarithromycin in patients with mild-to-moderate RTIs, our study indicated telithromycin 800 mg once daily had a statistically equivalent efficacy to the recommended regimen of clarithromycin for the treatment of mild-to-moderate community-acquired RTIs, and was generally well tolerated. Once-daily oral dosing of telithromycin may be a useful option for the empiric treatment of such community-acquired RTIs, potentiallymitigating against the emergence of resistant strains, and resulting in lower health-care costs.
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(Received September 28, 2012)
Edited by WANG Mou-yue and CUI Yi