Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

George G. Zhanel1,2,3,*, Christel Johanson1, Tamiko Hisanaga1, Chris Mendoza1, Nancy Laing1, Ayman Noreddin1, Aleksandra Wierzbowski1 and Daryl J. Hoban1,2

1Department of Medical Microbiology, Faculty of Medicine, University of Manitoba; Departments of 2 Clinical Microbiology and 3 Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada

Received 16 September 2004; accepted 21 September 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations.

Materials and methods: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (Cmax) 0.7 mg/L, t1/2 10 h; and free ELF: Cmax 6.0 mg/L, t1/2 10 h]. Starting inocula were 1 x 106 cfu/mL in Mueller–Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum).

Results: Telithromycin free serum concentrations achieved in the model were: Cmax 0.9±0.08 mg/L, AUC0–24 6.4±1.5 mg·h/L and t1/2 of 10.6±1.6 h. Telithromycin free ELF concentrations achieved in the model were: Cmax 6.6±0.8 mg/L, AUC0–24 45.5±5.5 mg·h/L and t1/2 of 10.5±1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0–1.9 log10 reduction in inoculum compared with a 3.0–3.3 log10 reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating Cmax/MIC ≥14.1 and area under the curve to MIC (AUC0–24/MIC) ≥100 [time above the MIC (t > MIC) of 100%], were bactericidal (≥3 log10 killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae.

Conclusion: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving Cmax/MIC ≥14.1 and AUC0–24/MIC ≥100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.

Keywords: S. pneumoniae , mef(A) , erm(B) , respiratory tract infections , ketolides


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Streptococcus pneumoniae is an important cause of community-acquired respiratory tract infections, such as community-acquired pneumonia, acute sinusitis and acute otitis media.15 Initially, all S. pneumoniae isolates were exquisitely susceptible to penicillin (MIC ≤0.06 mg/L), and ß-lactams served as the treatment of choice for S. pneumoniae infections.1 Beginning in the 1960s, however, resistance to penicillin and other agents began to be reported and has spread rapidly worldwide, especially during the past 5 years.615

Macrolide (azithromycin, clarithromycin and erythromycin) resistance in S. pneumoniae is presently ~25% in the USA and ~13% in Canada.1315 Macrolide resistance in S. pneumoniae involves alteration of the ribosomal target site, or production and utilization of an efflux mechanism.1619 The production of ribosomal methylase, which alters the ribosomal target site of the macrolide, is usually coded for by the erm(B) gene and confers broad macrolide, lincosamide and streptogramin B resistance.17,19 The second mechanism, which results in macrolide efflux, is coded for by the mef(A) gene.17,19 Efflux is macrolide specific (14- and 15-membered macrolides only) and does not affect the lincosamide or streptogramins (M-phenotype).17,19 It is also important to note that erm(B)-positive S. pneumoniae generally exhibit high-level (MIC90 ≥ 64 mg/L) macrolide resistance, whereas mef(A)-positive S. pneumoniae exhibit low to moderate-level resistance (MIC90 4 mg/L).1719 Both of these mechanisms are transmissible to other isolates.18,19 Presently, in North America, mef(A)-positive S. pneumoniae are more common than erm(B)-positive S. pneumoniae and mef(A) and erm(B) strains make up the majority of macrolide-resistant S. pneumoniae.18,19 In Europe, the erm(B)-positive S. pneumoniae are more prevalent.18,19

Although reports associating macrolide-resistant S. pneumoniae with macrolide clinical failure in the treatment of community-acquired respiratory infections are available, they are not common.20 Ketolides are a new class of semi-synthetic agents derived from erythromycin A and are designed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides.17,2125 The main structural difference between ketolides and the macrolides is the lack of L-cladinose sugar at position 3 of the erythronolide A ring and its replacement with a 3-keto group.17,21,22 Telithromycin and cethromycin (formerly ABT-773) have excellent in vitro activity against many pathogens causing community-acquired respiratory infections, including penicillin and macrolide-resistant strains.17,21,22 Ketolides demonstrate potent activity against most macrolide-resistant streptococci, including erm(B)- and mef(A)-positive S. pneumoniae.17,21,22 Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing.21,22,26,27 Presently, only limited data are available on the pharmacodynamic activity of ketolides against macrolide-resistant S. pneumoniae in comparison with macrolides.28,29

The purpose of this study was to assess the pharmacodynamic activity of the ketolide, telithromycin, simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations against macrolide-resistant S. pneumoniae.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Bacterial strains and culture conditions

Two macrolide-susceptible and six macrolide-resistant strains of S. pneumoniae were evaluated (Table 1). Isolates were obtained from the Canadian Respiratory Organism Susceptibility Study (CROSS).1314 Telithromycin and azithromycin MICs are depicted in Table 1. The wild-type strains, 11771 and 11888, were PCR-negative for both mef(A) and erm(B) and were macrolide-susceptible (azithromycin MIC ≤0.5 mg/L). Macrolide-resistant (azithromycin MIC ≥2 mg/L) strains were PCR-positive for either mef(A) or erm(B) (Table 1). Isolates were chosen to represent a variety of macrolide resistance phenotypes (MICs 2–256 mg/L). The method and conditions used for PCR detection of mef(A) and erm(B) genotypes have been described previously.19


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Table 1. Telithromycin and azithromycin susceptibilities of macrolide-susceptible and macrolide-resistant S. pneumoniae

 
Antibiotic preparation and susceptibility testing

Antibiotics were obtained as laboratory grade powders from their respective manufacturers. Stock solutions were prepared and dilutions made according to previously described methods.30 Following two subcultures from frozen stock, antibiotic MICs were determined by the NCCLS broth microdilution method.30,31 All MIC determinations were performed in triplicate on separate days.

In vitro pharmacodynamic model

The in vitro pharmacodynamic model used in this study has been described previously.32,33 Logarithmic phase cultures were prepared using a 0.5 McFarland (1 x 108 cfu/mL) standard by suspending several colonies in cation-supplemented Mueller–Hinton broth with 2% lysed horse blood (pH 7.1; Oxoid, Nepean, Ontario, Canada). This suspension was diluted 1:100 and 20 µL of the diluted suspension was further diluted in 60 mL of cation-supplemented Mueller–Hinton broth with 2% lysed horse blood. The resulting suspension was allowed to grow overnight at 35°C in ambient air.32,33 After a maximum of 17 h, the suspension was further diluted to 1:10, and 60 mL of the diluted suspension was added to the in vitro pharmacodynamic model. Viable bacterial counts consistently yielded a starting inoculum of ~1 x 106 cfu/mL.32,33 This final inoculum was introduced into the central compartment (volume, 610 mL) of the in vitro pharmacodynamic model.

Pharmacokinetics and pharmacodynamics simulated

Telithromycin was modelled based upon data obtained from previous publications (our target or simulated concentrations), simulating a dosage of 800 mg by mouth once daily for free serum (serum protein binding ~70%17,21,22 [maximum concentration (Cmax) 0.7 mg/L, t1/2 10 h] and free ELF (Cmax 6.0 mg/L, t1/2 10 h).17,21,22,26 Antibiotic was added to the central compartment at concentrations simulating clinically achievable free drug in serum and ELF. As the protein binding of telithromycin in ELF was not known, it was assumed to be equivalent to that of serum (~70%) and the concentration simulated in ELF was only free drug (non-protein bound fraction). Pharmacodynamic experiments were performed in ambient air at 37°C. Samples were collected at 0, 1, 2, 4, 6, 12, 24 and 48 h for both pharmacokinetic and pharmacodynamic assessment.32,33 Telithromycin concentrations in the pharmacodynamic model were determined microbiologically with a bioassay.27,32,33 Actual or achieved telithromycin concentrations were determined in quadruplicate using Bacillus subtillis ATCC 6633 as the test organism with lower limits of quantification of 0.03 mg/L. The plates were incubated aerobically for 18 h at 37°C. Concentrations were determined in relation to the diameters of the inhibition zones caused by the known concentrations from the standard series. The correlation coefficient of this assay was 0.80. Intra- and interrun variabilities of quality control samples were ≤6.5% and ≤5.8%, respectively. The actual or achieved concentrations of telithromycin and not the target or simulated concentrations were used in pharmacodynamic interpretations (e.g. Cmax/MIC and AUC0–24/MIC). Pharmacodynamic parameters: Cmax/MIC, area under the curve to MIC (AUC0–24/MIC) and time above the MIC (t > MIC) were derived from the actual or achieved telithromycin concentrations obtained in the model relative to the MIC for the strain in question.

Pharmacodynamic sampling was performed over 48 h with viable bacterial counts assessed by plating serial 10-fold dilutions onto cation-supplemented Mueller–Hinton agar with 2.0% lysed horse blood. Plates were incubated for 24 h at 37°C in ambient air. The lowest dilution plated was 0.1 µL of undiluted sample and the lowest level of detection was 200 cfu/mL (2.0 log10).32,33


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Table 1 shows the MICs of telithromycin and azithromycin against the eight clinical isolates utilized in this study. Strains were chosen to include macrolide-susceptible (wild-type) as well as low-level (MIC 2–4 mg/L), intermediate (MIC 8 mg/L) and high-level (MIC 16 mg/L) macrolide-resistant mef(A) strains and erm(B)-positive S. pneumoniae. As shown in Table 1, all mef(A) strains were susceptible to clindamycin.

Pharmacokinetics

Target (simulated) and actual (achieved) pharmacokinetic parameters of telithromycin after simulating a dosage of 800 mg by mouth once daily (free serum and free ELF) achieved in the model were similar (Table 2). Target (simulated) and actual (achieved) pharmacokinetic parameters of telithromycin achieved in serum were as follows: free drug Cmax 0.7 mg/L, AUC0–24 4.5 mg h/L, t1/2 10 h and Cmax 0.9 ± 0.08 mg/L, AUC0–24 6.4 ± 1.5 mg·h/L, t1/2 10.6 ± 1.6 h, respectively. Telithromycin target (simulated) and actual (achieved) pharmacokinetic parameters achieved in free ELF were: Cmax 6.0 mg/L, AUC0–24 38.6 mg·h/L, t1/2 10 h and Cmax 6.6 ± 0.8 mg/L, AUC0–24 45.5 ± 5.5 mg·h/L, t1/2 10.5 ± 1.7 h, respectively.


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Table 2. Simulated (target) and achieved (actual) telithromycin pharmacokinetics

 
Pharmacodynamics

Table 3 describes the killing of S. pneumoniae with telithromycin concentrations with the achieved free-drug concentrations in serum and ELF. Free serum concentrations of telithromycin resulted in a 1.0–1.9 log10 cfu/mL decrease versus initial inoculum at 2 h and complete bacterial eradication (≥4.0 log10 cfu/mL decrease versus initial inoculum) of all macrolide-susceptible and macrolide-resistant strains at 4, 6, 12, 24 and 48 h. Free ELF concentrations of telithromycin resulted in bacterial killing (3.0–3.3 log10 cfu/mL decrease versus initial inoculum) at 2 h and complete bacterial eradication (≥4.0 log10 cfu/mL decrease versus initial inoculum) of all macrolide-susceptible and macrolide-resistant strains at 4, 6, 12, 24 and 48 h.


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Table 3. Telithromycin killing of S. pneumoniae simulating free serum and epithelial lining fluid concentrations

 
The pharmacodynamic parameters associated with bacterial inhibition (decrease log10 cfu/mL at 24 h versus initial inoculum) by telithromycin simulating the achieved free serum as well as free ELF concentrations of telithromycin are depicted in Tables 46. As can be observed from Tables 46, free telithromycin serum and ELF concentrations simulating t > MIC of 100%, Cmax/MIC ≥14.1 and AUC0–24/MIC ≥ 100 were bactericidal (≥3 log10 killing) at 24 h (or 48 h, data not shown).


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Table 4. Pharmacodynamics of telithromycin versus macrolide-susceptible and macrolide-resistant S. pneumoniae (t > MIC)

 

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Table 6. Pharmacodynamics of telithromycin versus macrolide-susceptible and macrolide-resistant S. pneumoniae (AUC0–24/MIC) Serum-free drug ELF-free drug

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The purpose of this study was to assess the pharmacodynamic activity of telithromycin simulating clinically achievable concentrations of free drug in serum and ELF against macrolide-resistant S. pneumoniae. We clearly showed that telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of macrolide resistance phenotype (Table 3). Specifically, free telithromycin serum and ELF concentrations simulating Cmax/MIC ≥ 14.1 and AUC0–24/MIC ≥ 100 (t > MIC of 100%), were bactericidal (≥3 log10 killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae.

Comparing the ketolide telithromycin with the macrolide azithromycin, we previously reported that azithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae, but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype.33 It should, however, be mentioned that our model simulates an immunocompromised host as no component of the immune system is added to the model. Thus, whether azithromycin can eradicate macrolide-resistant S. pneumoniae in an immunocompetent host is not known. As the majority of S. pneumoniae in North America are macrolide-susceptible (~75% in the USA and ~87% in Canada), this may help to explain the excellent bacteriological and clinical outcomes obtained with macrolides (such as azithromycin) versus comparator antibiotics in clinical studies of community-acquired respiratory infections, such as community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis and otitis media, where S. pneumoniae is a key pathogen.17 However, the rapid and extensive eradication of macrolide-resistant S. pneumoniae [whether mef(A) or erm(B)] by telithromycin, when simulating clinically achievable free drug in serum and ELF in this study, suggests that ketolides offer an advantage compared with macrolides such as azithromycin, which is not able to eradicate macrolide-resistant S. pneumoniae [whether mef(A) or erm(B)] in serum, ELF or middle ear fluid.33 These differences may help explain why ketolides, when compared with macrolides, may result in reductions in hospitalization rates when treating community-acquired pneumonia.34,35

Only limited data are available regarding the pharmacodynamic properties of ketolides such as telithromycin.29,3639 Jacobs et al.37 demonstrated that against Gram-positive cocci such as S. pneumoniae, telithromycin demonstrated post-antibiotic effects of 0.3–3.8 h and post-antibiotic sub-MIC effects of 0.8–4.6 h. It has been demonstrated that telithromycin is a concentration-dependent bacterial killer with eradication being related to AUC/MIC and Cmax/MIC.29,39 Odenholt et al.39 reported that against S. pneumoniae, telithromycin demonstrated extremely fast (~1 h) bactericidal (≥3 log10 killing) activity with Cmax/MIC ≥ 37.5. In this study, we also observed very rapid bactericidal activity, with complete eradication of S. pneumoniae from the model within 4 h, simulating free telithromycin serum and ELF pharmacodynamics of Cmax/MIC ≥14.1 and AUC0–24/MIC ≥ 100 (Tables 5 and 6). We also chose to describe the telithromycin t > MIC obtained in the model (100%) even though this pharmacodynamic parameter has not been demonstrated to be the most relevant for telithromycin, unlike macrolides such as clarithromycin and erythromycin (Table 4).17,33


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Table 5. Pharmacodynamics of telithromycin versus macrolide-susceptible and macrolide-resistant S. pneumoniae (Cmax/MIC)

 
In conclusion, telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving Cmax/MIC ≥14.1 and AUC0–24/MIC ≥100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The expert secretarial assistance of M. Tarka is appreciated. This study was supported in part by the University of Manitoba.


    Footnotes
 
* Correspondence address. Microbiology, Health Sciences Centre, MS673 – 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. Tel: +1-204-787-4902; Fax: +1-204-787-4699; Email: ggzhanel{at}pcs.mb.ca


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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34 . Tellier, G., Chang, J. R., Asche, C. V. et al. (2004). Comparison of hospitalization rates in patients with community acquired pneumonia treated with telithromycin for 5 or 7 days or with clarithromycin for 10 days. Current Medical Research and Opinion 20, 739–47.[CrossRef][ISI][Medline]

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