1 Zoom International Clinical Research Group, 290 Montigny Street, Saint-Jerome, Quebec J7Z 5T3, Canada 2 Department of Medicine, Winthrop University Hospital, Mineola, NY; 3 State University of New York at Stony Brook, NY; 4 Aventis, Bridgewater, NJ, USA
Received 7 July 2003; returned 1 September 2003; revised 6 April 2004; accepted 21 April 2004
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Abstract |
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Methods: This was a multicentre, randomized, double-blind, active-controlled study. Patients with mild to moderate CAP received telithromycin 800 mg once a day for 5 (n=193) or 7 (n=195) days or clarithromycin 500 mg twice a day for 10 days (n=187). In these groups, 159, 161 and 146 patients, respectively, completed the study.
Results: At the post-therapy/test-of-cure evaluation, clinical cure rates (per-protocol clinical population) were 89.3% (5 days) and 88.8% (7 days) for telithromycin, and 91.8% for clarithromycin 10 days. Satisfactory bacteriological outcome rates (per-protocol bacteriological population) were 87.7% and 80.0% for 5 and 7 days of telithromycin, respectively, and 83.3% for 10 days of clarithromycin. Bacteriological eradication rates in the respective treatment groups were, for Streptococcus pneumoniae, 95.8% (23/24), 96.7% (29/30) and 88.5% (23/26); for Haemophilus influenzae, 88.0% (22/25), 84.0% (21/25) and 88.2% (15/17) and for Moraxella catarrhalis, 1/1, 4/5 and 3/4. Both telithromycin regimens demonstrated clinical efficacy against pneumococcal bacteraemia (19/19), atypical pathogens (9/9) and erythromycin-resistant S. pneumoniae isolates (5/5). Most treatment-emergent adverse events were mild to moderate in intensity with most commonly reported adverse events involving the gastrointestinal system.
Conclusions: Telithromycin 800 mg administered once a day for 5 or 7 days was as effective and safe as clarithromycin 500 mg administered twice a day for 10 days in treating patients with CAP caused by common respiratory pathogens, including macrolide-resistant isolates, and pneumococcal bacteraemia.
Keywords: ketolides , macrolides , antimicrobial resistance , pneumococcal pneumonia , bacteraemia , atypical , intracellular pathogens
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Introduction |
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The most frequently identified pathogen associated with CAP is Streptococcus pneumoniae.3,4 Other common aetiological agents include Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and atypical/intracellular pathogens (Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila).4,5 The wide range of causative pathogens and the emergence of bacterial resistance to currently available antibiotics are critical factors in the choice of initial drug therapy for CAP. Furthermore, there is considerable variation in the magnitude and types of resistance (e.g. pneumococcal resistance) among nations and regions worldwide.68 The clinical symptomology of CAP does not permit the clinician to differentiate between infections caused by typical pathogens and those caused by atypical/intracellular pathogens or strains resistant to current antibiotics.9 The use of diagnostic studies to establish the causative pathogens of CAP during initial patient assessment at the clinician's office or even in an acute-care facility remains controversial due to lack of rapid, convenient, accurate, widely available and cost-effective methods that provide immediate results.1012 Therefore, in the community setting, CAP is usually treated empirically.1,11,12
Empirical selection of antibiotics for the initial treatment of CAP often results in the use of an agent that is not active against the entire spectrum of possible causative pathogens.13 Resistance of S. pneumoniae, H. influenzae and M. catarrhalis to antibiotic treatment has been documented globally.14 The emergence of antibiotic-resistant pathogens is a worldwide problem with variations in local prevalence. Infection with penicillin-resistant pneumococci has been found to increase the risk of suppurative complications in hospitalized adults with bacteraemic pneumococcal pneumonia.15 Thus, ideally, an antibiotic selected empirically for the treatment of CAP should be active against common respiratory pathogens as well as against resistant strains and atypical/intracellular pathogens.
Antibiotic treatment regimens for CAP can be lengthy, ranging from 7 to 10 days, depending on the agent.12 However, shorter treatments have also been successful.1618 The disadvantages of longer treatments include the emergence of drug-related adverse effects19 and low compliance rates.16 Low compliance and too short a treatment duration are both factors that may increase the likelihood of only partial eradication of the pathogen19 and the promotion of drug resistance.
The ketolides are a new class of antibacterial agents developed for the treatment of community-acquired respiratory tract infections, including CAP. Telithromycin, the first member of this class, has a tailored spectrum of activity covering common (typical) and atypical/intracellular respiratory tract pathogens, including resistant strains.20 The pharmacokinetics and tissue penetration of telithromycin permit once-a-day administration over a short duration.21,22 Telithromycin in a 710 day course of treatment has been shown to be effective in CAP, yielding a reported clinical cure rate ranging from 88 to 95%.23 Bacterial cure rates of 88%,24 94.3%24 and 90%24 have been achieved for M. catarrhalis, S. pneumoniae and H. influenzae, respectively. Safety and tolerability have been demonstrated in Phase III clinical trials.23 The 5 day telithromycin regimen was chosen on the basis of the pharmacokinetic profile of telithromycin.22 The long half-life (10 h)22 and good tissue penetration into white blood cells and alveolar macrophages provide for adequate tissue concentrations of telithromycin at 48 h after the last dose.21 The 7 day telithromycin20,2325 and 10 day clarithromycin26 regimens were chosen for their proven efficacy in CAP infections.
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Materials and methods |
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The primary objective of this study was to determine the equivalence in clinical efficacy between oral telithromycin (given at a dose of 800 mg once daily for 5 or 7 days) and oral clarithromycin (given at a dose of 500 mg twice daily for 10 days) and to assess the safety of these regimens in the treatment of CAP in adult patients. The secondary objective was to compare the bacteriological efficacy of the treatments for common/typical and atypical/intracellular pathogens.
Study design
This was a multicentre, double-blind, active-controlled, three-arm, parallel-group (1:1:1) study. Five visits were scheduled: a pre-therapy/entry visit (day 1), an on-therapy visit (days 35), an end-of-therapy visit (days 1113), a test-of-cure (TOC) visit (days 1721) and a late post-therapy visit (days 3136). Nine countries (Argentina, Brazil, Canada, Chile, Germany, South Africa, Spain, UK and USA) hosted the 77 investigational sites that participated in the study, which was conducted between December 1999 and April 2001. Patients were managed in both hospital and outpatient settings.
During the pre-therapy/entry visit, subjects were assessed for eligibility and signed informed consent. Demographical and medical history data were obtained, and a routine physical examination, including measurement of vital signs, was performed. Chest X-rays were taken, and an evaluation of current infection was completed. Microbiological samples of sputum or respiratory secretions were collected for Gram's stain, cultures and antimicrobial susceptibility testing; blood samples were taken for bacteriological culture and serology testing. All samples were analysed by the local microbiology laboratories of the investigating centres using tests for culture and identification as described elsewhere.27 Identification and antibiotic susceptibilities of the three main pathogens (i.e. S. pneumoniae, H. influenzae, and M. catarrhalis) were confirmed by a central microbiology reference laboratory. Antibiotic susceptibilities were determined by disc diffusion and broth microdilution methods in accordance with NCCLS guidelines as appropriate.28 Samples were analysed to detect atypical/intracellular pathogens by polymerase chain reaction (PCR)29,30 testing in addition to microimmunofluorescence techniques (to detect C. pneumoniae) and enzyme-linked immunosorbent assay (ELISA) (to detect M. pneumoniae).
Clinical laboratory testing, urinalysis and pregnancy testing were performed on blood and urine samples, as appropriate. A 12-lead electrocardiogram (ECG) was performed if the patient was taking class III antiarrhythmic agents, antiarrhythmic agents affecting or affected by the cytochrome P450 (CYP) 2D6 pathway, CYP3A4 pathway inhibitors (ketoconazole, itraconazole, fluconazole, ritonavir) or digoxin. Baseline and concurrent medication use was documented. At the study visits, the investigators monitored changes in pneumonia symptoms and status, reviewed medication adherence, assessed safety and conducted routine examinations for overall assessment of health. These evaluations were performed at all five visits.
Respiratory/sputum and blood samples obtained within 48 h before the initiation of treatment were used for isolation, identification and susceptibility testing of causative pathogens. During and after treatment, repeat samples were taken from all sites with positive cultures prior to entry. Two sets of blood samples of at least 10 mL were taken for culture by separate venipuncture no less than 15 min apart. Patients were diagnosed with an atypical/intracellular pathogen if they had a negative aerobic culture for any typical pathogen from a respiratory specimen and if they met the following criteria: (i) a diagnosis of C. pneumoniae, based on a four-fold increase in microimmunofluorescence immunoglobulin G (IgG)/immunoglobulin M (IgM) (polyclonal) titres of paired sera or a single IgM titre of 1:32 in combination with a positive PCR for the pathogen; (ii) a diagnosis of M. pneumoniae, based on a four-fold increase in paired serum IgG titres or a single IgM titre of
1:16 in combination with a positive PCR for the pathogen; or (iii) a diagnosis of L. pneumophila, based on a four-fold increase in paired serum IgG or IgM titres or a positive urine antigen for L. pneumophila serogroup 1.
Patient selection
The study patients were hospitalized or outpatient male or female adults, 18 years of age, with clinical and chest X-ray findings compatible with a diagnosis of CAP. Data for one 15-year-old subject who was inadvertently entered into the study were included in the results. Target enrolment was 516 patients (172 per treatment arm), with the goal of obtaining
120 clinically evaluable patients per treatment arm.
Inclusion criteria required the new onset of at least two of the following clinical signs and symptoms: cough, auscultatory finding such as rales or evidence of pulmonary consolidation (i.e. dullness on percussion, bronchial breath sounds, egophony); dyspnoea or tachypnoea, particularly if progressive in nature; fever [oral temperature > 38°C (100.4°F), tympanic temperature > 38.5°C (101.2°F) or rectal temperature > 39°C (102.2°F)]; total peripheral white blood cell (WBC) count > 10 000/mm3 or >15% immature neutrophils (bands), regardless of total peripheral WBC count. Subjects were also required to have a diagnosis of acute CAP based on production of purulent sputum and chest X-ray findings supporting a clinical diagnosis of bacterial pneumonia, such as the presence of a new infiltrate. Women of childbearing potential were required to have a negative urine pregnancy test.
Patients were excluded if they were pregnant or lactating, had concomitant diseases that would preclude proper assessment of the disease under study, had CAP requiring admission to the intensive care unit (ICU), or were receiving parenteral antibiotic treatment. Patients were also excluded if they had significant respiratory or neurological complications, were immunocompromised, were allergic to the study medications or had received more than 24 h of treatment with other antibiotics within 7 days before study enrolment. Waiver of the above inclusion and exclusion criteria needed documented approval by the investigator and sponsor on a case-by-case basis before the patient could be enrolled.
The clinical study protocol, informed consent documents and any other appropriate study-related documents were reviewed and approved by an independent ethics committee/institutional review board. Informed consent was obtained before the conduct of any study-related procedures.
Antimicrobial therapy
Patients were randomized (1:1:1) to receive telithromycin 800 mg (two 400 mg capsules) once a day for 5 days plus matching placebo for 5 days, telithromycin 800 mg (two 400 mg capsules) once a day for 7 days plus matching placebo for 3 days or clarithromycin 500 mg (two 250 mg capsules) twice a day for 10 days. In this double-blind design, placebo was added on all days in the telithromycin groups to blind treatment for the twice-daily administration of clarithromycin and once-daily treatment with telithromycin.
Efficacy criteria
The primary efficacy measure was clinical outcome at the post-therapy/TOC visit in the per-protocol clinical (PPc) population. Clinical cure was defined as either the return to the pre-infection state (i.e. all pneumonia-related signs and symptoms had disappeared and chest X-ray findings had shown improvement) or improvement in related post-infectious stigmata, such that residual symptoms if any did not require additional treatment and were accompanied by improvement or lack of progression based on chest X-ray. The secondary efficacy measure was bacteriological outcome at the post-therapy/TOC visit in the per-protocol bacteriological (PPb) population. Satisfactory bacteriological outcome at post-therapy/TOC was defined as either: (i) absence of causative pathogen (eradication); (ii) clinical improvement to such an extent that a proper follow-up culture could not be obtained (presumed eradication) or (iii) isolation of a bacterial strain other than the primary causative pathogen with the subject having no signs or symptoms of active infection (colonization).
Safety assessment
Adverse events reported by the patient or noted by the investigator were the primary safety measure. The safety assessment was based on patient evaluation, physical examination, vital signs, 12-lead ECG in patients taking selected concomitant medications at pre-therapy/entry and clinical laboratory data (including haematology, blood chemistry and urinalysis). The safety population consisted of all patients who had received at least one dose of the study medication and who had at least one post-baseline clinical or laboratory safety assessment.
Statistical procedures
The sample size calculation was based on equivalence testing for clinical cure rates at the post-therapy/TOC visit (PPc population). Sample size justification assumed an expected cure rate of 85% in each of any two treatment groups and a lower equivalence margin of 15%. In accordance with this assumption, the sample size per treatment group was calculated to be 120 subjects. This sample size would provide with 90% power that each of any two treatments could be confirmed as equivalent if the lower limit of the 95% confidence interval (CI) was 15% or greater and the upper limit crossed zero. The total number of subjects enrolled depended on the dropout rate. A total of 516 subjects were predicted to provide adequate power, with the assumption that at least 70% of the subjects treated would be clinically evaluable for efficacy at post-therapy/TOC.
The modified intent-to-treat (mITT) analysis was performed on data from all patients who had a confirmed diagnosis of CAP and who received at least one dose of the study medication. Two subpopulations were defined from the per-protocol population. The per-protocol population analysed for clinical outcome (PPc population) consisted of mITT patients without major protocol violations. The per-protocol population analysed for bacteriological outcome (PPb population) included PPc patients with a causative pathogen isolated from an adequate culture at pre-therapy/entry.
To assess the comparability of the three treatment groups, baseline demographic and prognostic variables were summarized for each treatment group by an analysis of variance (ANOVA) for the continuous variables (i.e. age, body mass index and weight) and the CochranMantelHaenszel test for categorical variables (i.e. sex, race, pneumonia severity and chest X-ray findings). Clinical outcome at the post-therapy/TOC visit in the PPc population was assessed by a closed procedure for multiple comparisons with two-sided 95% CI. Two treatments were considered equivalent if the lower limit of the two-sided 95% CI on the difference in response rates was greater than 15% and the upper bound was greater than 0. Equivalence between each of the telithromycin groups and the clarithromycin group was analysed in a stepwise fashion. The first comparison paired the 7 day telithromycin group and the clarithromycin group. If the two-sided 95% CI did not conclude equivalence, testing was stopped. If the first comparison concluded equivalence, a second comparison between the 5 day telithromycin group and the clarithromycin group was performed. Conclusions were drawn accordingly. No adjustment for the type I error rate (CI coverage probability) was required to maintain the overall probability of incorrectly concluding equivalence at 2.5%, one sided. An analysis of clinical outcome at the post-therapy/TOC visit in the mITT population was also performed to further support the findings in the PPc population. Safety data (adverse events, clinical laboratory variables and vital signs) were summarized by descriptive statistics.
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Results |
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A total of 581 patients were enrolled, and 575 patients were randomized to one of the three treatment groups (5 day telithromycin, n=193; 7 day telithromycin, n=195; 10 day clarithromycin, n=187). The primary reason for not randomizing an enrolled patient was the absence of chest X-ray findings consistent with CAP. All randomized patients received at least one dose of study medication. Baseline demographic characteristics in the mITT population were not significantly different between the groups (Table 1). The distribution of patients according to Fine score31 was consistent with the severity expected for outpatients treated with oral antibiotics (Table 2). Primary disease characteristics in this population are presented in Table 2. Compliance rates for patients taking 100% of the medication for the duration of the study were 92.0% for the telithromycin 5 day group, 90.1% for telithromycin 7 days and 85.1% for clarithromycin 10 days.
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Consistent with findings from epidemiological studies,4,12,32 S. pneumoniae, H. influenzae and M. catarrhalis together made up 60% of the causative pathogens isolated at pre-therapy/entry in this study. In the PPb population, there were 65 individuals each in the telithromycin groups and 54 patients in the clarithromycin group in whom causative pathogens were isolated. The total numbers of pathogens isolated were 82 for the telithromycin 5 day group, 95 for the telithromycin 7 day group and 77 for the clarithromycin 10 day group. S. pneumoniae was the most frequently isolated common respiratory pathogen in telithromycin 7 day and the clarithromycin 10 day groups (30 and 26, respectively), followed by H. influenzae (25 and 17, respectively), then M. catarrhalis (5 and 4, respectively). In the telithromycin 5 day group, the most frequently isolated common respiratory pathogens were H. influenzae (25), S. pneumoniae (24) and M. catarrhalis (1). There were five, five and three S. aureus isolates in the telithromycin 5 day, telithromycin 7 day and clarithromycin 10 day groups, respectively. Other pathogens (i.e. isolates recovered in cultures from sputum meeting the definition of adequate and identified by investigators as causative, but which may not be generally recognized as pathogenic in patients with this type of infection) identified in the study were 27, 30 and 27 in the telithromycin 5 day, telithromycin 7 day and clarithromycin 10 day groups, respectively. In vitro antimicrobial susceptibility data (Table 3) for common respiratory pathogens were based primarily on testing conducted at the central laboratory as determined by a broth microdilution technique.
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The primary efficacy analysis of clinical outcome at the post-therapy/TOC visit in the PPc population demonstrated equivalence between telithromycin 800 mg once a day for either 5 or 7 days and clarithromycin 500 mg twice a day for 10 days in adult patients with CAP (95% CI, telithromycin 5 day treatment 9.7, 4.7; telithromycin 7 day treatment 10.2, 4.3). In the 466 PPc patients who completed the study, the clinical cure rates at post-therapy/TOC were 89.3% (142/159 patients) in the 5 day telithromycin group, 88.8% (143/161 patients) in the 7 day telithromycin group and 91.8% (134/146 patients) in the 10 day clarithromycin group (Tables 4 and 5). These results were supported by the analysis of clinical outcome at the post-therapy/TOC visit in the mITT population, which also showed equivalence in clinical efficacy between the groups: 82.4% (154/187 patients), 82.2% (157/191 patients) and 81.2% (147/181 patients) for the telithromycin 5 and 7 day and the clarithromycin 10 day regimens, respectively.
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A secondary efficacy variable was bacteriological outcome in the PPb population at the post-therapy/TOC visit. Rates of satisfactory bacteriological outcome were 87.7% (57/65 patients) in the 5 day telithromycin group, 80.0% (52/65 patients) in the 7 day telithromycin group and 83.3% (45/54 patients) in the 10 day clarithromycin group.
At post-therapy/TOC, the eradication rates for the common (typical) causative pathogens of CAP were as follows: for S. pneumoniae, 95.8% (23/24 patients) in the 5 day telithromycin group, 96.7% (29/30 patients) in the 7 day telithromycin group and 88.5% (23/26 patients) in the 10 day clarithromycin group; for H. influenzae, the rates were 88.0% (22/25 patients), 84.0% (21/25 patients) and 88.2% (15/17 patients), and for M. catarrhalis, the rates were 100.0% (1/1 patient), 80.0% (4/5 patients) and 75.0% (3/4 patients), respectively.
Eradication of pathogens resistant to macrolides
A total of seven patients (accounted for in all PPb patients and among mITT patients who had at least one infective pathogen based on bacteriological sampling) had S. pneumoniae isolates (single and mixed pathogens) resistant to erythromycin A at pre-therapy/entry: three patients in the 5 day telithromycin group and two patients each in the 7 day telithromycin and 10 day clarithromycin groups. No S. pneumoniae isolates resistant to penicillin G were observed in this study.
At post-therapy/TOC, all five telithromycin patients with erythromycin-resistant S. pneumoniae isolates and one of the two clarithromycin patients with erythromycin-resistant S. pneumoniae isolates achieved bacteriological eradication and clinical cure. The telithromycin MIC values for the erythromycin-A (macrolide)-resistant S. pneumoniae (ERSP) isolates in the 5 day and 7 day groups were 0.12 and
0.5 mg/L, respectively. The one patient with erythromycin-resistant S. pneumoniae bacteraemia who received clarithromycin was a clinical failure; the pneumonia worsened and septic arthritis developed, requiring treatment with iv antimicrobial agents.
Eradication of atypical/intracellular pathogens
The clinical cure rates for patients with atypical/intracellular pathogens at the post-therapy/TOC visit in the PPc population were as follows: for C. pneumoniae, one patient each in all three groups; for M. pneumoniae, 3/3 patients in both the 5 and 7 day telithromycin groups and 2/3 patients in the clarithromycin group; and for L. pneumophila, 1/1 patient in the 7 day telithromycin group.
Clinical outcome in patients with bacteraemia or demographic factors of special interest
At the post-therapy/TOC visit, the clinical cure rate for the 25 patients (19 patients in the telithromycin groups and six patients in the clarithromycin group) in the PPc population with documented bacteraemia with S. pneumoniae was 100.0% in the telithromycin groups and 66.7% in the clarithromycin group (Figure 1). All patients with documented S. pneumoniae bacteraemia in the telithromycin groups (12 patients in the 5 day group and seven patients in the 7 day group) had both bacteriological eradication and clinical cure. As mentioned (see Eradication of pathogens resistant to macrolides), the one patient with erythromycin-resistant S. pneumoniae bacteraemia [MIC = 512 mg/L, genotype erm(A)/erm(B)] in the clarithromycin group was considered a clinical failure as, despite treatment, the pneumonia worsened on day 6 and was complicated by the development of septic arthritis (with S. pneumonia being isolated from related purulent discharge). This patient was hospitalized and therapeutic measures instituted which resulted in eventual clinical cure included discontinuation of study medication and switching to intravenous antibiotics (gentamicin, ceftazidime, metronidazole, penicillin G and cefuroxime). Clinical cure rates in patients who were 65 years of age were similar to, although not as high as, those in the overall patient population. The cure rates for patients
65 years old were 82.1% (23/28 patients), 73.9% (17/23 patients) and 90.0% (27/30 patients) for the telithromycin 5 and 7 day and the clarithromycin groups, respectively (Figure 1). Clinical cure rates in patients with a Fine score of
III were comparable across treatment groups at the post-therapy/TOC evaluation (Figure 1).
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Among the 575 randomized patients, 257 patients (44.7%) experienced at least one treatment-emergent adverse event (TEAE). The numbers of patients with TEAEs and the rates of occurrence are summarized in Table 6. Most TEAEs were mild or moderate in intensity. The most frequently reported TEAEs were gastrointestinal in nature (diarrhoea, nausea and dysgeusia). In the telithromycin groups, all diarrhoea, nausea and dysgeusia events were mild or moderate in intensity, and none was severe or categorized as serious. Two events of diarrhoeaone in each telithromycin groupresulted in discontinuation; in the clarithromycin group, there were no discontinuations due to gastrointestinal events.
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There were 25 treatment failures for which a cause was reported. In 22 of the 25 patients (89%), the cause was reported as signs, symptoms and/or chest X-ray findings not resolved. In the remaining three patients, the cause was reported as incorrect diagnosis, one for possible tuberculosis, one for cardiac oedema requiring bypass (day 33) and one for atypical pneumonia. No serious, possibly treatment-related TEAEs occurred in the telithromycin groups. One patient in the clarithromycin group experienced a serious TEAE that was possibly treatment related, as determined by the investigator. The patient had a severe psychotic reaction (mania) on day 3 of treatment. The medication was discontinued on day 3 and symptoms resolved with no sequelae on day 16. The investigator stated that although psychotic reaction was unlikely to be due to the study medication, the relationship could not be ruled out.
Five patients experienced adverse events leading to death during the study: one patient in the telithromycin 5 day group and two patients each in the telithromycin 7 day and the clarithromycin 10 day groups. A patient in the 5 day telithromycin group died from Klebsiella spp. septicaemia. This patient was enrolled into the study before the sputum culture result was available. On day 3, cultures revealed Klebsiella pneumoniae resistant to telithromycin and clarithromycin. Despite administration of alternative iv antibiotics and other therapeutic measures, the patient died. In the 7 day telithromycin group, one patient died from cardiac arrest on day 3. Prior to the administration of telithromycin, it was noted that this patient had underlying heart disease including cardiac enlargement, renal insufficiency (CLCr=29 mL/min) and first-degree heart block. The other patient in this group who died had a history of seizures. For unknown reason, the patient was found to have stopped taking the study medication 2 days prior to developing convulsions on day 7. The patient was then started on iv antibiotics and diazepam as well as other countermeasures. The patient died on the following day from clinically diagnosed acute meningitis (the family did not agree to a lumbar puncture). Among the two deaths in the clarithromycin group, one patient died from lung cancer on day 30 (during the post-treatment period) and the other patient suffered a myocardial infarction resulting in death 3 days after completion of treatment. The study investigators reported that the deaths in the telithromycin and clarithromycin groups were attributable to underlying disease states and were not related to treatment.
The most frequently reported, possibly treatment-related TEAEs (2% incidence in at least one treatment cohort) involved the gastrointestinal system (Table 7). These occurred in 15.0% (29/193) of patients in the 5 day telithromycin group, 13.3% (26/195) of patients in the 7 day telithromycin group and 11.8% (22/187) of patients in the 10 day clarithromycin group.
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Discussion |
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Guidelines from the Infectious Diseases Society of America, the American Thoracic Society and the Centers for Disease Control and Prevention provide recommendations for surveillance and management of CAP in the current era of emerging drug-resistant respiratory pathogens.12,34 All three guidelines recommended the use of macrolide (or doxycycline) as first-line treatment for outpatients diagnosed with CAP. Doxycycline is regarded as an alternative choice even though it has less reliable activity against pneumococcus; in general, it should be reserved for patients who are allergic to or intolerant of the macrolides. However, with the emergence of macrolide resistance in S. pneumoniae, new alternative therapies should be explored and developed.
Telithromycin, a ketolide antibiotic, has a targeted spectrum of activity, providing coverage for both common and atypical/intracellular respiratory pathogens, including resistant S. pneumoniae.20,3537 At the molecular level, ketolides differ from macrolides by the carbamate extension and by replacement of the L-cladinose moiety at position 3 of the erythronolide A ring with a keto group.38 Both erythromycin and telithromycin bind to domain V of rRNA. The carbamate extension on telithromycin forms an additional contact at domain II,39 thereby providing an additional mechanism for disrupting bacterial protein synthesis. The chemical structure of telithromycin confers activity against pathogens resistant to macrolides.
The current study demonstrated equivalence in clinical efficacy between telithromycin 800 mg given once a day for either 5 or 7 days and clarithromycin 500 mg given twice a day for 10 days when used to treat adult patients with mild to moderate CAP. Satisfactory bacterial eradication rates were also comparable across the three treatment groups. Telithromycin was effective in patients with erythromycin-resistant organisms, as the two telithromycin regimens eradicated all five resistant isolates. In the clarithromycin group, only one of the two resistant isolates was eradicated. Although relatively few atypical organisms were isolated among the three treatment groups, eradication of these organisms was high in telithromycin- and clarithromycin-treated patients.
Patients in the current study experienced comparable side effects regardless of treatment randomization, and no patient in either telithromycin group was determined by the investigators to have experienced a serious adverse event related to the treatment drug. The safety profile of telithromycin in the treatment of CAP in this study was similar to that seen in previously conducted Phase III clinical trials.23,25
The telithromycin 5 day regimen was associated with high response rates in patients whose infection was due to common respiratory pathogens, including macrolide-resistant S. pneumoniae. Moreover, in special interest populations, the 5 day telithromycin regimen resulted in comparable clinical cure rates (population with a Fine score of III and
65 years of age) to those with the 10 day course of clarithromycin. Furthermore, numerically higher compliance rates (92.0%) were observed with the 5 day telithromycin when compared with the 7 day telithromycin (90.1%) and 10 day clarithromycin (85.1%) regimens.
In summary, this study showed comparable clinical efficacy and safety between the shorter-course telithromycin (5 day and 7 day) and longer-course clarithromycin (10 day) regimens in the treatment of CAP. Further, telithromycin achieved satisfactory bacteriological outcome in patients with CAP caused by common respiratory pathogens. Telithromycin 800 mg once daily for 5 or 7 days provides a safe, efficacious and convenient treatment option for the management of mild to moderate CAP.
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Footnotes |
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References |
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