International Journal of Infectious Diseases
Volume 13, Issue 4 , Pages 483-487, July 2009

Pharmacodynamic target attainment potential of azithromycin, clarithromycin, and telithromycin in serum and epithelial lining fluid of community-acquired pneumonia patients with penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae☆

  • Ayman M. Noreddin

      Affiliations

    • College of Pharmacy, University of Minnesota, 1110 Kirby Dr., Duluth, MN 55812, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 218 726 6028; fax: +1 218 726 6500.
    • ,
  • Walid F. El-Khatib

      Affiliations

    • College of Pharmacy, University of Minnesota, 1110 Kirby Dr., Duluth, MN 55812, USA
    • Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt
    • ,
  • Jason Aolie

      Affiliations

    • College of Pharmacy, University of Minnesota, 1110 Kirby Dr., Duluth, MN 55812, USA
    • ,
  • Ahmed H. Salem

      Affiliations

    • College of Pharmacy, University of Minnesota, 1110 Kirby Dr., Duluth, MN 55812, USA
    • Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt
    • ,
  • George G. Zhanel

      Affiliations

    • Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Received 25 May 2008; received in revised form 31 July 2008; accepted 15 August 2008. published online 01 December 2008.

Corresponding Editor: William Cameron, Ottawa, Canada

Article Outline

Summary 

Objective

To compare the probability of target attainment (PTA) for macrolides and ketolides against penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae in both serum and epithelial lining fluid (ELF) of patients with community-acquired pneumonia (CAP).

Methods

Monte Carlo simulations were used to assess the attainment of the bacterial eradication-linked pharmacodynamic index of the free drug area under the concentration–time curve over 24hours to minimum inhibitory concentration (fAUC0–24/MIC90) by azithromycin, clarithromycin, and telithromycin, at therapeutic doses, against penicillin-susceptible, intermediate, and resistant S. pneumoniae.

Results

In serum, azithromycin and clarithromycin were found to have a probability of attaining the recommended fAUC0–24/MIC90 ratio of 30 in 50.2% and 74.6%, respectively, of CAP patients with penicillin-intermediate strains, and a probability of 36.9% and 60.7%, respectively, in cases of penicillin-resistant strains. Telithromycin maintained a probability of reaching the fAUC0–24/MIC90 ratio of 30 in serum and ELF in 89.1% of CAP patients, regardless of the penicillin resistance of the strain.

Conclusions

Clarithromycin results in a higher PTA than azithromycin in the treatment of penicillin-susceptible S. pneumoniae, but both of these agents exhibit a decreasing efficacy as S. pneumoniae penicillin resistance increases. When compared to clarithromycin and azithromycin, telithromycin maintains higher PTA in CAP patients with penicillin-resistant strains of S. pneumoniae.

Keywords: Macrolides, Ketolides, Streptococcus pneumoniae, Monte Carlo simulation, Bacterial resistance

 

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Introduction 

Streptococcus pneumoniae is currently a leading causative organism of a wide range of community-acquired bacterial infections, including pneumonia, otitis media, sinusitis, bacteremia, and meningitis.1, 2 The morbidity and mortality associated with S. pneumoniae infections continues to place a heavy socioeconomic burden on the world community.3 Many different serotypes of S. pneumoniae are capable of causing infection and all of them were at one time susceptible to penicillin. Resistance of S. pneumoniae to penicillin first began to develop in the 1960s and has been increasing rapidly among isolates in the last two decades.4, 5 Penicillin resistance rates especially increased throughout the 1990s. Penicillin-intermediate strains of S. pneumoniae increased from 3.8% in 1989 to 27.8% in 1997,6, 7 while penicillin-resistant strains of S. pneumoniae increased from 2.6% in 1992 to 21.5% in 2000.8, 9

Studies have shown that S. pneumoniae isolates resistant to penicillin are also resistant to macrolide antibiotics.10 Azithromycin and clarithromycin exhibited a MIC90 (minimum inhibitory concentration required to inhibit the growth of 90% of isolates) of >64μg/ml against penicillin-resistant strains, while in cases of penicillin-susceptible strains the MIC90s were 1μg/ml and 0.25μg/ml, respectively.10 The growing resistance of S. pneumoniae to penicillins and macrolides has led to the development of a new class of antibiotics called the ketolides. Telithromycin was the first approved antibiotic in this class. It shows good activity against penicillin-resistant strains of S. pneumoniae with a MIC90 <0.25μg/ml and has a low probability of inducing macrolide-type resistance.10

Pharmacodynamic studies indicate that the ratio of the area under the concentration–time curve of the free drug over 24hours to the MIC90 (fAUC0–24/MIC90) correlates best with the efficacy of azithromycin and telithromycin therapy.11, 12, 13 With reference to clarithromycin, studies have reported using fAUC0–24/MIC90, percent time above the MIC (%T > MIC), or the ratio of peak serum concentration of the antimicrobial agent to the MIC of the agent (Cmax/MIC) for predicting therapeutic efficacy.14, 15, 16, 17 In 2002, and after an extensive pharmacodynamic study, Tessier et al. suggested that fAUC0–24/MIC90 is the best parameter for predicting clarithromycin efficacy since it incorporates both duration and intensity of exposure.17 A target range of 25–35 for the fAUC0–24/MIC90 ratio was shown to be required for azithromycin and clarithromycin in order to achieve bacterial eradication and a positive clinical outcome in patients with S. pneumoniae-associated community-acquired pneumonia (CAP).18 For telithromycin, Lodise et al. indicated that an fAUC0–24/MIC90 ratio of 3.375 is adequate in predicting bacterial eradication in S. pneumoniae infections.19 This difference is suggested to be due to the ability of telithromycin to better penetrate and increase concentration at the infection site or differences in protein binding. However, when pharmacokinetic modeling was used in the same study to better account for telithromycin drug penetration, a target fAUC0–24/MIC90 ratio of about 27 for bacterial eradication was estimated.19

With the continuing rise in penicillin resistance among S. pneumoniae isolates, it is important to evaluate the ability of macrolides and ketolides to achieve a favorable clinical outcome against resistant strains in S. pneumoniae-related infections. The purpose of this study was to compare the pharmacodynamic target attainment potential of azithromycin, clarithromycin, and telithromycin at the standard doses to achieve fAUC0–24/MIC90 of ≥30, ≥40, and ≥100 in both serum and the epithelial lining fluid (ELF) against penicillin-susceptible (PS), penicillin-intermediate (PI), and penicillin-resistant (PR) S. pneumoniae in CAP patients.

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Materials and methods 

Pharmacokinetic simulations 

Published pharmacokinetic parameters of azithromycin, clarithromycin, and telithromycin were used to simulate the distribution of the free drug exposure measures (fAUC0–24) in both serum and ELF when given to CAP patients at doses of 500/250mg once daily, 500mg twice daily, and 800mg once daily, respectively.20

Pharmacodynamic simulations 

Susceptibility data of azithromycin, clarithromycin, and telithromycin against PS, PI, and PR S. pneumoniae were obtained from the Canadian Respiratory Organism Susceptibility Study (CROSS).21, 22 CROSS is a longitudinal national surveillance program that studies the incidence of antibiotic resistance in respiratory pathogens across all regions of Canada. The outcome linked parameter, fAUC0–24/MIC90, of the tested drugs was estimated by dividing the simulated fAUC0–24 values by the MIC90 values obtained from the CROSS study.

Monte Carlo simulation analysis 

A Monte Carlo simulation of a 10000 patient population was performed to determine the percentage of patients achieving an fAUC0–24/MIC90 ratio of ≥30, ≥40, and ≥100 in both serum and ELF after the previously described azithromycin, clarithromycin, and telithromycin dosing regimens and evaluated against PS, PI, and PR S. pneumoniae. Monte Carlo simulations were performed using Professional Crystal Ball 2000 program (Decisioneering UK Ltd, London, UK).23, 24, 25 Using Monte Carlo simulation allowed for complete accountability of the MIC distribution of S. pneumoniae isolates as well as the variability in drug exposure among CAP patients.

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Results 

The probability of attainment of the fAUC0–24/MIC90 target ratios for azithromycin, clarithromycin, and telithromycin against PS, PI, and PR S. pneumoniae are shown in Table 1 and Figure 1, Figure 2.

Table 1. Probability of target attainment (PTA, %) of fAUC0–24/MIC90 ratios for azithromycin, clarithromycin, and telithromycin at standard therapeutic doses in serum and ELF of CAP patients with penicillin-susceptible (PS), penicillin-intermediate (PI), and penicillin-resistant (PR) Streptococcus pneumoniae.
PTA in serum (%)PTA in ELF (%)
PSPIPRPSPIPR
Drug/dose304010030401003040100304010030401003040100
Azithromycin 500/250mg, once daily81.481.369.950.240.60.036.926.80.082.381.98053.052.449.438.738.237.2
Clarithromycin 500mg, twice daily91.389.284.774.669.361.260.756.046.899.999.993.983.083.080.372.372.370.5
Telithromycin 800mg, once daily99.098.696.095.494.287.989.184.273.910010099.899.899.899.199.899.898.8

fAUC0–24, free drug area under the concentration–time curve over 24hours; MIC90, minimum inhibitory concentration required to inhibit the growth of 90% of isolates; ELF, epithelial lining fluid; CAP, community-acquired pneumonia.

  • View full-size image.
  • Figure 1. 

    Probability of attainment of the fAUC0–24/MIC90 target of 30 for azithromycin, clarithromycin, and telithromycin in the serum of community-acquired pneumonia patients with penicillin-susceptible (PS), penicillin-intermediate (PI), and penicillin-resistant (PR) Streptococcus pneumoniae.

  • View full-size image.
  • Figure 2. 

    Probability of attainment of the fAUC0–24/MIC90 target of 30 for azithromycin, clarithromycin, and telithromycin in the epithelial lining fluid of community-acquired pneumonia patients with penicillin-susceptible (PS), penicillin-intermediate (PI), and penicillin-resistant (PR) Streptococcus pneumoniae.

Penicillin-susceptible S. pneumoniae 

For azithromycin 500/250mg once daily, the probability of achieving an fAUC0–24/MIC90 ratio of 30 in serum was 81.4% and in ELF was 82.3%, but it decreased to be 69.9% in serum and 80% in ELF when the target value was set to 100. With reference to clarithromycin 500mg twice daily, the probability of achieving a target value of 30 in serum was 91.3% and in ELF was 99.9%, and at a target value of 100, it was 84.7% in serum and 93.9% in ELF. Telithromycin use of 800mg once daily had a probability of achieving an fAUC0–24/MIC90 of 30 in 99% and 100 in 96% in serum, and an fAUC0–24/MIC90 of 30 in 100% and 100 in 99.8% in ELF.

Penicillin-intermediate S. pneumoniae 

Azithromycin 500/250mg once daily had a probability of 50.2% and 0.0% in serum and 53.0% and 49.4% in ELF for achieving the target values of 30 and 100, respectively. Clarithromycin use at 500mg twice daily yielded a probability of 74.6% and 61.2% in serum and 83.0% and 80.3% in ELF at the target values of 30 and 100, respectively. Telithromycin use of 800mg once daily had a probability of 95.4% and 87.9% in serum and 99.8% and 99.1% in ELF at fAUC0–24/MIC90 of 30 and 100, respectively.

Penicillin-resistant S. pneumoniae 

Use of azithromycin 500/250mg once daily in the Monte Carlo simulation had a probability of 36.9% and 0.0% in serum and 38.7% and 37.2% in ELF for achieving fAUC0–24/MIC90 of 30 and 100, respectively. Clarithromycin use of 500mg twice daily yielded a probability of 60.7% and 46.8% in serum and 72.3% and 70.5% in ELF at the target values of 30 and 100, respectively. Telithromycin use of 800mg once daily had a probability of 89.1% and 73.9% in serum and 99.8% and 98.8% in ELF at fAUC0–24/MIC90 of 30 and 100, respectively.

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Discussion 

Studies have shown that bacterial eradication can be predicted by the relationship between the pathogen's MIC and drug exposure.26, 27 Pharmacodynamic studies indicate that the fAUC0–24/MIC90 ratio correlates best with predicting efficacy of azithromycin, clarithromycin, and telithromycin therapy.11, 12, 13, 17 Pharmacodynamic study data for azithromycin and clarithromycin has shown an fAUC0–24/MIC90 ratio of 25–35 to be necessary to predict bacterial eradication and a positive clinical outcome in patients with S. pneumoniae-associated CAP.18 For telithromycin, an fAUC0–24/MIC90 ratio of 27 was found to be adequate in predicting bacterial eradication in S. pneumoniae infections.19

When simulating the pharmacodynamics of these agents in serum and ELF of CAP patients with PI S. pneumoniae, our data showed variability in the probability of target attainment (PTA) between these agents (Table 1). The Monte Carlo simulation data show that azithromycin can only reach the suggested fAUC0–24/MIC90 ratio of 30 in 50.2% of patients. Using clarithromycin increases the probability of attaining the fAUC0–24/MIC90 ratio of 30 to 74.6% of patients. Simulating administration of the ketolide telithromycin increases the probability of attaining the fAUC0–24/MIC90 ratio of 30 against PI S. pneumoniae to 95.4%.

In the pharmacodynamic simulations of these agents in serum and ELF of CAP patients with PR S. pneumoniae, our data indicate an even greater difference in the PTA than with the PI strains (Table 1). Azithromycin Monte Carlo simulation data predict only a 36.9% chance of achieving the fAUC0–24/MIC90 ratio of 30 to produce bacterial eradication, and clarithromycin treatment only has a probability of target attainment of 60.7% in the serum of CAP patients. In contrast, according to our data, the newer ketolide telithromycin maintains a high probability of reaching the fAUC0–24/MIC90 ratio of 30 in serum and ELF at 89.1% of CAP patients with PR strains.

Based on these findings we conclude that all three of these agents are adequate in producing a high probability of achieving a favorable clinical outcome at normal therapeutic doses in serum and ELF of CAP patients with PS strains of S. pneumoniae. Clarithromycin results in better pharmacodynamic target attainment than azithromycin, but both of these agents exhibit a decreased probability of achieving the fAUC0–24/MIC90 ratio of 30, which is predictive of bacterial eradication, as S. pneumoniae penicillin resistance increases.

The lower pharmacodynamic target attainment potential of azithromycin can lead to the selection of resistant mutants resulting in higher potential for the development of bacterial resistance. These findings are consistent with other clinical findings that showed higher probability for the selection of macrolide resistance when azithromycin was used vs. clarithromycin or erythromycin and hence, patients treated with azithromycin were more likely to have macrolide-resistant organisms.28 Telithromycin 800mg once daily maintains a high probability of pharmacodynamic target attainment against PR strains of S. pneumoniae, and thus from a bacteriological eradication perspective, other ketolides such as cethromycin need to be evaluated for potential target attainment against PR strains of S. pneumoniae. This study only evaluated the efficacy of azithromycin, clarithromycin, and telithromycin against S. pneumoniae possessing different levels of penicillin resistance. Further studies are required to evaluate the efficacy against S. pneumoniae strains that are resistant to other drug classes.

Conflict of interest: No conflict of interest to declare.

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☆ This study was presented at the International Society of Chemotherapy Third International Conference on Community Acquired Pneumonia (ISC-CAP), April 14–16, 2007, Montreal, Quebec, Canada.

PII: S1201-9712(08)01540-3

doi:10.1016/j.ijid.2008.08.016

International Journal of Infectious Diseases
Volume 13, Issue 4 , Pages 483-487, July 2009

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