Community-acquired respiratory tract infections caused by resistant pneumococci: clinical and bacteriological efficacy of the ketolide telithromycin

Charles M. Fogarty1,*, Shigeru Kohno2, Patricia Buchanan3, Michel Aubier4 and Malik Baz5

1 Spartanburg Pharmaceutical Research, 126 Dillon Street, Spartanburg, SC 29307; 3 River Road Medical Group, Eugene, OR; 5 ABM Research Institute, Fresno, CA, USA; 2 Nagasaki University School of Medicine, Nagasaki, Japan; 4 Xavier Bichat School of Medicine, Paris, France

Received 26 June 2002; returned 25 September 2002; revised 28 November 2002; accepted 20 December 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The incidence of community-acquired respiratory tract infections caused by Streptococcus pneumoniae exhibiting antibacterial resistance has increased dramatically in recent years. Telithromycin is the first of a new class of antibacterials, the ketolides, which have been developed specifically to provide effective treatment for these infections. Data were analysed from 3935 patients who had participated in one Japanese Phase II study and 11 US/global Phase III studies in three indications: community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Patients received either telithromycin 800 mg once daily or a comparator antibacterial. S. pneumoniae isolates considered to be causative for infection were tested for susceptibility to penicillin G and erythromycin A. In per-protocol analyses, telithromycin showed a high level of clinical efficacy against S. pneumoniae, with clinical cure rates of 92.8% for all isolates, 91.7% for those with reduced susceptibility to penicillin G and 86.0% for those with reduced susceptibility to erythromycin A. Bacterial eradication rates were consistent with the clinical outcomes. High rates of clinical cure and bacterial eradication were also observed for infections caused by isolates demonstrating high-level resistance to erythro-mycin A [MICs >= 512 mg/L: 100% (13/13) clinical cure, 100% (13/13) bacterial eradication]. These results support the use of telithromycin as a first-line oral therapy for the treatment of community-acquired respiratory tract infections caused by S. pneumoniae with reduced susceptibility to penicillin G and erythromycin A.

Keywords: telithromycin, ketolide, resistant S. pneumoniae, clinical efficacy, bacteriological efficacy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Community-acquired respiratory tract infections (RTIs) are among the most prevalent infectious diseases in the developed world and constitute a substantial socioeconomic burden. Each year in the USA, for example, there are an estimated 31 million cases of acute sinusitis.1 Lower RTIs [community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB)] are more serious, accounting for nearly half of all community-acquired infections, and are the leading cause of death from infectious diseases in the USA.2 In 1990, lower RTIs were responsible for 4.3 million premature deaths worldwide.3

Streptococcus pneumoniae remains the most frequent bacterial cause of community-acquired RTIs. It is the major bacterial cause of CAP and has been estimated to be responsible for between 20 and 40% of cases in North America and Europe.2,46 Among patients with AECB and acute sinusitis, S. pneumoniae is estimated to be responsible for ~15–25% and 30–40% of cases, respectively.7,8 In recent years, antibacterial resistance in S. pneumoniae has spread globally at an increasing rate;911 the current overall prevalence of penicillin resistance (MIC >= 2.0 mg/L) is 39.9%.12 Similarly, erythromycin A resistance, which can confer cross-resistance to other macrolide–lincosamide–streptogramin (MLS) agents, including clarithromycin and azithromycin, has been reported as 37.9%.12 In the USA, macrolide resistance rates doubled between 1995 and 1999.13 This increase in resistance rates has been accompanied by a trend towards higher erythromycin A MICs among resistant isolates.13 Resistance to fluoroquinolones has also emerged.12,14 For penicillin, macrolides and fluoroquinolones, an association between the number of prescriptions and the development of resistance has been reported14,15 and this may partly account for the wide geographical variation in resistance rates. Several recent reports have linked penicillin-, macrolide- and fluoroquinolone-resistant S. pneumoniae with poor clinical outcome and potentially fatal complications.1625 A recently published study found that in S. pneumoniae, macrolide resistance arising from efflux and methylase mechanisms is clinically relevant.25 These findings have resulted in an urgent need for new antibacterial agents for the current and future treatment of respiratory pneumococcal infections. Ideally, these agents should both retain activity against resistant pneumococci and have a low potential to induce, or select for, resistant and/or cross-resistant strains.

The ketolides represent a new class of antibacterials within the MLS group. Ketolides are derivatives of the semisynthetic 14-membered-ring macrolides with a keto group replacing the L-cladinose moiety at position 3 and a methoxy substituent at C6.26 Telithromycin is the first ketolide to be approved for clinical use and has been developed specifically for the effective treatment of RTIs. In addition to the structure described above, it has a carbamate extension at positions C11/C12.27 The keto group not only confers acid stability,28 but is also responsible for the fact that ketolides, unlike macrolides, do not induce MLS resistance in vitro.29,30 Furthermore, the addition of the C11/C12 carbamate side-chain to telithromycin enhances both its antibacterial activity and its binding to MLS-resistant ribosomes.3133

In vitro studies using telithromycin have shown it to exhibit potent activity against a range of key respiratory pathogens, including penicillin- and/or macrolide-resistant pneumococci (for review see Barman Balfour & Figgitt34). Telithromycin has also been demonstrated to have little potential to induce, or select for, resistant strains.35,36 Subsequently, a number of clinical trials have confirmed that telithromycin is effective in the treatment of CAP, AECB and acute sinusitis.34,3744

The aim of this study was to review the clinical and bacteriological efficacy of telithromycin 800 mg in the treatment of patients with community-acquired RTIs (CAP, AECB or acute sinusitis) caused by penicillin- and/or macrolide-resistant S. pneumoniae.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient population

The study population comprised 3885 patients [2695 telithromycin (mean age 44.3 years, range 13–99 years) versus 1190 comparator (mean age 48.0 years, range 15–97 years)] who had participated in 11 US/global Phase III studies in three indications: CAP, AECB and acute sinusitis (Table 1). The studies were approved by independent ethics committees in each country. Patients received either telithromycin or recommended comparator drugs at the time of the study (amoxicillin, co-amoxiclav, clarithromycin, cefuroxime axetil, trovafloxacin) (see Table 1 for dosage regimens). All of the studies involving comparator drugs were of a randomized, double-blind design. In contrast to the US/global clinical development programme for telithromycin, the Japanese clinical development programme included Phase II studies to determine the appropriate dose for this population. An additional 50 patients (mean age 52.8 years, range 18–79 years) who received telithromycin 800 mg in a Phase II study conducted in Japan were also included in the analysis of resistant S. pneumoniae isolates.


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Table 1.  Clinical trials analysed to evaluate the efficacy of telithromycin in treating penicillin G- and/or erythromycin A-resistant strains of S. pneumoniae
 
Pathogens were isolated at the screening visit from bacteriological cultures of blood, respiratory secretions or sinus aspirates. The common respiratory pathogens isolated from adequate respiratory samples and considered responsible for infection were defined as causative for infection by the investigator. Strains of S. pneumoniae were tested for their susceptibility to penicillin G and erythromycin A by MIC determination at a central reference laboratory using the NCCLS-recommended broth microdilution method.45 Isolates with a penicillin G MIC between 0.12 and 1.0 mg/L were interpreted as intermediately susceptible, whereas strains with MICs >= 2.0 mg/L were defined as fully resistant. Resistance to erythromycin A was defined as MIC >= 1.0 mg/L.

Clinical and bacteriological outcomes

Clinical and bacteriological outcomes were assessed at a post-therapy, test-of-cure (TOC) visit (days 17–24) in the Phase III studies and at the end of the therapy (day 7 or after discontinuation of treatment) in the Japanese Phase II study. A TOC visit in the Phase III studies at 17–24 days allowed early relapses to be captured and thus provided a rigorous test of antibacterial efficacy. Clinical cure was defined as the disappearance or return to pre-infection state of all signs and symptoms, with an improvement in chest X-ray findings or clinical and radiological amelioration, such that no further antibacterial treatment was needed. The bacteriological outcome was classed as satisfactory if the pathogen was shown to be eradicated, or if the patient improved clinically to the extent that a proper follow-up culture could not be obtained, in which case eradication was presumed to have occurred.

All patients with a confirmed diagnosis of CAP, AECB or acute sinusitis who had received at least one dose of the study medication were included in the modified intention-to-treat (mITT) population. Patients without major protocol deviations following randomization were included in the per-protocol (PP) analysis, whereas patients with an identified pre-therapy causative pathogen were included in the bacteriological modified intention-to-treat (bmITT) population. Patients with baseline S. pneumoniae infections were pooled across all indications to form a subgroup, since the 5- and 10-day telithromycin regimens were previously determined to be equivalent in terms of efficacy for the treatment of acute sinusitis.43 The clinical and bacteriological outcomes in these patients, including those with resistant strains, were determined. All analyses were completed descriptively.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient population

On the basis of bacteriological cultures of blood and respiratory secretions, a subgroup of 423 patients from the 3935 patients in the study population (10.8%; telithromycin, n = 333; pooled comparators, n = 90) was identified who had S. pneumoniae as the sole pathogen or as part of a mixed infection. Overall, in the telithromycin-treated patients, 23.1% (77/333) of S. pneumoniae strains showed reduced susceptibility to penicillin G and/or erythromycin A. In comparator-treated patients, 21.1% (19/90) of strains were similarly resistant. The majority of the resistant S. pneumoniae strains were isolated from patients with CAP [telithromycin, 40/77 (51.9%); comparators, 8/19 (42.1%)]. The remainder of resistant isolates from patients in the telithromycin treatment group were isolated from patients with acute sinusitis [37/77 (48.0%)]. In the comparator-treated group, four patients with AECB and seven with acute sinusitis were infected with resistant isolates.

A total of 12 patients with CAP had blood cultures positive for resistant S. pneumoniae. All of the isolates were found to be susceptible to telithromycin at a breakpoint of <=1 mg/L as defined in clinical study protocols.

Clinical and bacteriological outcome

For patients in the Phase III studies with S. pneumoniae infection (irrespective of penicillin G and/or erythromycin A susceptibility), clinical cure rates following telithromycin therapy were generally similar to the overall clinical cure rates for each indication (Table 2). Similar findings were observed for pooled comparators.


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Table 2.  Clinical cure ratesa at the test-of-cure visit for Phase III studies in which patients received telithromycin 800 mg once daily or a comparator antibacterialb for community-acquired RTIs
 
Twenty-five patients in telithromycin study groups and 12 patients in comparator study groups had indeterminate clinical responses and were excluded from the denominator for the calculation of clinical outcomes (Table 3). The main reasons for exclusion included inability to determine outcome at the TOC visit, not meeting the inclusion criteria for laboratory analyses and the use of non-study antimicrobials for infections other than RTIs.


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Table 3 . Clinical cure ratesa in patients who received telithromycin 800 mg once daily or a comparator antibacterialb for community-acquired RTIs caused by S. pneumoniae (as either the sole pathogen or as part of a mixed infection) with reduced susceptibility to penicillin G and/or erythromycin A
 
Telithromycin demonstrated high clinical efficacy against S. pneumoniae, irrespective of susceptibility to penicillin G and/or erythromycin A (PP: 92.8% for all S. pneumoniae versus 91.2% for strains with reduced susceptibility). In patients infected with S. pneumoniae that exhibited full resistance to penicillin G, the clinical cure rate of individuals treated with telithromycin compared favourably with that of patients who received a comparator in the PP population [83.9% (PENR/ERYS: 9/9; PENR/ERYR: 17/22) versus 71.4% (PENR/ERYS: 2/2; PENR/ERYR: 3/5), respectively] (Table 3). Similarly, in patients infected with S. pneumoniae that exhibited full resistance to erythromycin A, telithromycin demonstrated a favourable clinical cure rate compared with that of comparators in the PP population [86.0% (PENS/ERYR: 7/8; PENI/ERYR: 13/13; PENR/ERYR: 17/22) versus 81.8% (PENS/ERYR: 2/2; PENI/ERYR: 4/4; PENR/ERYR: 3/5), respectively] (Table 3).

Eight patients treated with a ß-lactam comparator antibiotic (amoxicillin, co-amoxiclav or cefuroxime) were infected with S. pneumoniae that exhibited full resistance to penicillin G. The clinical cure rate in these patients was 62.5% (PENR/ERYS: 2/3; PENR/ERYR: 3/5). Erythromycin A-resistant S. pneumoniae strains were isolated from three patients treated with a macrolide comparator antibiotic (clarithromycin) and clinical cure was achieved in all three patients (PENS/ERYR: 1/1; PENI/ERYR: 1/1; PENR/ERYR: 1/1).

The effects of telithromycin and comparators on bacterial eradication rates in patients whose infections were caused by strains of S. pneumoniae with reduced susceptibility to penicillin G and/or erythromycin A were consistent with the clinical cure rates (Table 4).


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Table 4. Bacteriological eradication rates in patients who received telithromycin 800 mg once daily or a comparator antibacteriala for community-acquired RTIs caused by S. pneumoniae (as either the sole pathogen or as part of a mixed infection) with reduced susceptibility to penicillin G and/or erythromycin A
 
Telithromycin was found to be clinically and bacteriologically effective against erythromycin A-resistant isolates, irrespective of erythromycin A MIC (n = 43; range 2– >512 mg/L, mode > 512 mg/L). For isolates with erythromycin A MICs >= 512 mg/L, rates of telithromycin clinical cure and bacterial eradication (documented or presumed) were 13/13 (100.0%) and 13/13 (100.0%), respectively.

A total of 44 patients in the telithromycin group had S. pneumoniae isolated from their blood and 40 (90.9%) achieved a clinical and bacteriological cure. Only 13 patients in comparator antibiotic groups had blood cultures positive for S. pneumoniae, with 11 (84.6%) achieving a clinical and bacteriological cure. A total of 235 patients in the telithromycin group did not have S. pneumoniae detected in their blood, with 219 (93.2%) achieving a clinical and bacteriological cure. Fewer (59) patients in comparator groups had negative cultures for S. pneumoniae isolates in their blood; 51 (86.4%) achieved a clinical and bacteriological cure.

Clinical cure was achieved by 7/9 (77.8%) patients (PP population) with penicillin G- and/or erythromycin A-resistant S. pneumoniae isolated from their blood. Both clinical failures occurred in patients with S. pneumoniae resistant to both penicillin G and erythromycin A. Of the two patients classified as treatment failures, one had documented eradication of S. pneumoniae from the blood but was treated with another antibiotic because of the presence of Staphylococcus aureus in the urine and so was not a documented microbiological failure. No antibiotic-resistant S. pneumoniae isolates were detected in blood samples from patients in comparator groups.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The dilemma facing the clinician who must initiate therapy before culture results are available is that treatment for any RTI must cover S. pneumoniae, which is becoming increasingly resistant to ß-lactam and macrolide antibacterials.10 The situation is compounded by cross-resistance within and between classes of antibacterial agents, which further limits treatment options.

Telithromycin is the first ketolide antibacterial to be approved for clinical use. The present study demonstrates high rates of bacterial eradication in patients infected with S. pneumoniae, irrespective of penicillin G or erythromycin A susceptibility. Excellent levels of clinical cure paralleled the bacteriological efficacy, and these rates compared well with those seen with comparator drugs.

The structural features that differentiate telithromycin from macrolides may contribute to its efficacy.46 Both macrolides and ketolides bind directly to the bacterial ribosome and inhibit protein synthesis, with erythromycin A and telithromycin interacting with nucleotides in domains II and V of 23S rRNA.33 Although these two drugs bind to nucleotide A2058 in domain V in a similar manner, the domain II interaction with nucleotide A752 is different. Whereas erythromycin A binds through its cladinose moiety, for telithromycin the carbamate extension is involved and confers superior binding in vitro.32 This may account for the good activity of telithromycin against MLS-resistant strains of pneumococci, as some binding capacity to ribosomes that are mutated in domain V is retained.32,47 In this study, good clinical efficacy was observed against erythromycin A-resistant isolates with high erythromycin A MICs (>512 mg/L). There have been recent reports that the macrolide MICs of erythromycin A-resistant pneumococci are increasing.13,48 Macrolides such as clarithromycin and azithromycin would not be expected to achieve high enough concentrations in blood or respiratory tissues to be effective against these pathogens. The poor serum concentration of azithromycin following oral administration may give rise to breakthrough bacteraemia in patients who are more seriously ill.49 Furthermore, according to a recent study of macrolide treatment failures, breakthrough bacteraemia is more likely to occur in patients with erythromycin-resistant pneumococci and, as a result, macrolide resistance is clinically relevant.25 This suggests that the incidence of macrolide clinical failures due to resistance could potentially increase.

It has been demonstrated that telithromycin does not induce MLS resistance in vitro,29 a property attributable to the replacement of the macrolide L-cladinose moiety with a 3-keto structure. In addition, the combination of the methoxy substituent at C6 with the 3-keto group confers excellent acid stability on the molecule,28 providing it with a degree of protection in the gastrointestinal environment and enabling the drug to achieve high concentrations at the site of infection.

In the treatment of RTIs, the goal is eradication of the pathogens with high rates of clinical cure, preventing progression to complications that may increase morbidity and necessitate hospitalization. For instance, 10–20% of patients with CAP subsequently develop bacteraemia, which is associated with an increased risk of mortality.50 Any first-line oral treatment that can limit such disease progression is of particular value.

In this study, oral telithromycin demonstrated high clinical and bacteriological efficacy in the treatment of community-acquired RTIs, including those caused by strains of S. pneumoniae with reduced susceptibility to penicillin G and/or erythromycin A. Rates of clinical cure and bacteriological eradication against such pathogens in patients treated with telithromycin were excellent, even against highly resistant isolates (erythromycin A MIC > 512 mg/L) that macrolides, such as clarithromycin and azithromycin, would not be expected to provide activity against. Erythromycin-resistant S. pneumoniae was recently demonstrated to be a risk factor for treatment failure in patients receiving macrolide therapy.25 Given that potency against drug-resistant pneumococci is likely to become an increasingly important factor when selecting empirical therapy for the treatment of community-acquired RTIs, the findings of this study support the use of telithromycin as a reliable first-line oral therapy for the treatment of these infections. The convenience of a once-daily dose and a short course of treatment (5 days) for patients with AECB or acute sinusitis has the potential to improve patient compliance and thus minimize the spread of resistance.


    Acknowledgements
 
This study was supported by a grant from Aventis.


    Footnotes
 
* Corresponding author. Tel: +1-864-583-1556; Fax: +1-864-583-2292; E-mail: cmf{at}bonetesting.com Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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