Good transfer of tebipenem into middle ear effusion conduces to the favorable clinical outcomes of tebipenem pivoxil in pediatric patients with acute otitis media
Rinya Sugita Received: 20 April 2012 / Accepted: 22 October 2012 / Published online: 8 February 2013
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2013
Abstract
Tebipenem pivoxil, an oral carbapenem anti- biotic for pediatric use, exhibits excellent clinical effects on acute otitis media (AOM). The present study was con- ducted to assess the pharmacokinetic profile of tebipenem in middle ear effusion and to examine the clinical efficacy of tebipenem pivoxil by calculating the values of the pharmacokinetic-pharmacodynamic parameters (AUC/MIC, Cmax/MIC, and T [ MIC) of tebipenem at the site of action. Twenty-three pediatric outpatients diagnosed with AOM were enrolled. Ear discharge or nasopharyngeal swabs collected before the onset of oral administration were used to conduct bacteriological examinations, and subjects were then treated by twice-a-day oral administra- tion of tebipenem pivoxil 6 mg/kg. The clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae were obtained from 10 and 19 pediatric patients (8 over- lapped), respectively. On day 2 of administration, blood and middle ear effusion were collected from 20 pediatric patients to measure plasma and middle ear concentrations of tebipenem. Consequently, the Cmax and the AUC0–? in plasma were 5.3 ± 1.6 lg/ml (mean ± SD) and 7.9 ± 0.2 lg h/ml, respectively. The Cmax in middle ear effusion of tebipenem was 1.2 ± 0.1 lg/ml, exceeding its MIC for these pathogens. The ratio of AUC0–? in middle ear effusion to AUC0–? in plasma was 0.36, showing the good transfer of tebipenem into the effusion; this result corrob- orated the known high rate of clinical efficacy of tebipenem pivoxil for patients with AOM and the low incidence of recurrence in them as manifested by the healing rate of 94.1 % (16/17).
Keywords : Tebipenem pivoxil · Acute otitis media · Middle ear effusion · Pharmacokinetics- pharmacodynamics
Introduction
Acute otitis media (AOM) is a representative upper respi- ratory tract infection that is frequently contracted by chil- dren. The major pathogens of AOM are Streptococcus pneumoniae and Haemophilus influenzae, and the number of pediatric patients who are resistant to antibiotic therapy is increasing in association with an increment in the number of drug-resistant bacteria.
Tebipenem pivoxil, the world’s first oral carbapenem antibiotic as the prodrug of tebipenem, has a broad anti- bacterial spectrum and shows potent antibacterial and bactericidal activities for penicillin-resistant S. pneumo- niae, macrolide-resistant S. pneumoniae, and b-lactamase- nonproducing ampicillin-resistant H. influenzae (BLNAR) [1, 2]. A clinical trial enrolling more than 300 pediatric
patients with otitis media, a condition in which the emer- gence of resistant bacteria is a concern, indicated a high clinical efficacy rate of 98.0 % and a high eradication rate of 100 % [3]. Tebipenem pivoxil was developed based on pharmacokinetic-pharmacodynamic (PK–PD) modeling, and its pharmacokinetics in plasma and its clinical efficacy have been analyzed in detail to examine their relationship
[3]. Tebipenem reached its peak plasma concentrations of 3.5 and 5.2 lg/ml at 0.7 h after oral administration of tebipenem pivoxil 4 and 6 mg/kg; the plasma concentra- tions decreased by half every 1 h [4]. Furthermore, a preclinical study using the mouse model of femoral infection [5] and a clinical trial [6] have clarified that the fAUC/MIC is a PK–PD parameter that most closely correlates with bacte- riological efficacy. The target fAUC/MIC and the PK–PD minimum inhibitory concentration (MIC) breakpoint for tebipenem are presumed to be 6 and 1.0 lg/ml, respectively [3, 6]. However, the pharmacokinetics of tebipenem at the site of infection in otitis media has not been analyzed.The objectives of the present study were to examine the relationship between the pharmacokinetics of tebipenem in middle ear effusion and its plasma concentrations, as well as the clinical efficacy of tebipenem pivoxil.
Patients and methods
Pediatric patients
Twenty-three pediatric outpatients (12 boys and 11 girls), who presented with the chief complaint of earache from April through August 2010 and who were diagnosed with AOM based on the presence of middle ear effusion and obvious reddening of the eardrum according to the 2004 Guidelines for the Diagnosis and Management of Acute Otitis Media [7], were enrolled in the present study. Pathology and severity were classified according to the 2009 Clinical Practice Guidelines for the Diagnosis and Treat- ment of Acute Otitis Media in Children [8]. Furthermore, the present study was conducted after acquisition of the approval from the institutional review board and in compliance with the ethical principles based on the Declaration of Helsinki. Oral and/or written informed consent was obtained from the parental guardian of the pediatric patient.
Assessments and measurements
Ear discharge or nasopharyngeal swab was collected on the first day of examination, and bacteria were then isolated and identified at Kitasato Institute for Life Sciences, Kitasato University. The MICs of antibiotics were mea- sured for S. pneumoniae and H. influenzae that were identified or presumed as pathogens.Tebipenem pivoxil 6 mg/kg was administered orally twice daily for 5 days. On day 2 of administration, laser- assisted tympanic membrane fenestration was conducted at 0.5–4.8 h after the immediately prior administration to col-ka, absorption rate constant; CL/F, apparent oral clearance; Vd/F, apparent volume of distribution of the central compartment; Tlag, time lag in absorption concentrations, patient background (age, 1.58 ± 1.14 years; creatinine clearance of pediatric patients was assumed to be 3.72 ml/min/kg [4]), and the population pharmacokinetic parameters reported by Sato et al. [4] (Table 1) were used to estimate the pharmacokinetic parameters for plasma tebip- enem in each pediatric patient according to the Bayesian estimation method. The pharmacokinetic model used was the one-compartment model with first-order absorption. NONMEN version 7.1.0 and PREDPP version 7.1.0 (Icon, Dublin, Ireland) were used to conduct pharmacokinetic analyses. Plasma concentrations of free tebipenem were calculated by multiplying plasma tebipenem concentration by the serum free fraction of tebipenem (=0.33) [4]. Fur- thermore, the transfer rate constant of tebipenem from plasma to middle ear effusion (kp–m) and the transfer rate constant of tebipenem from middle ear effusion to plasma (km–p) were estimated according to the deconvolution method. Namely, kp–m (h-1) and km–p (h-1) were estimated by minimizing the square sum of deviations of the calculated concentrations in middle ear effusion according to the fol- lowing formula and observed concentrations with Excel 2003 (Microsoft, Redmond, WA, USA): When 0 B t \ Tlag T(t) = 0 and when Tlag B t T (t)= A · D · kp—m[{e(kel—km—p)·(t—Tlag) — 1}· e—kel·t /(kel — km—p) middle ear effusion. Blood was collected into the heparinized blood-collecting tube concurrently (3.7 ± 7.6 min after collection of middle ear effusion), and the blood col- lected was centrifuged (1,000 g, 5 °C, 10 min) to obtain apparent volume of distribution of the central compartment (l/kg), and kel is elimination rate constant (h-1).
Pharmacokinetic parameters, dose, and the MICs were used to calculate three PK–PD parameters: AUC/MIC, Cmax/MIC, and time above MIC (T [ MIC).The clinical effects of tebipenem pivoxil were assessed in 17 pediatric patients who were reexamined on the day of administration completion or the next day thereof. AOM was considered ‘‘healed’’ when middle ear effusion and findings of otitis media (reddening of the eardrum and earache) disappeared and ‘‘unhealed’’ in other cases.
Results
Subjects were 5 months to 5 years and 3 months of age (mean ± SD, 1.7 ± 1.1 years) and ranged between 7.5 and 20 kg in body weight (mean ± SD, 10.8 ± 2.6 kg). According to the pathological classifications listed on the 2009 Clinical Practice Guidelines for the Diagnosis and Treatment of Acute Otitis Media in Children [7], there were 19 cases of simple AOM, as well as 4 cases of recurrent otitis media over the past 12 months or 3 cases of recurrent otitis media over the past 6 months; according to the severity classifications listed on the guidelines, there were 21 and 2 cases of severe otitis media and moderate otitis media, respectively (Fig. 1). All pediatric patients were concurrently afflicted with rhinosinusitis; that is, they presented with respiratory symptoms (e.g., nasal conges- tion, nasal discharge, postnasal discharge, and cough), headache, and cheek pain. The MIC90 values of tebipenem for 10 clinical isolates of S. pneumoniae and for 19 clinical isolates of H. influenzae, which were presumed to be pathogens removed from ear discharge or nasopharyngeal swab, were 0.06 lg/ml (range, 0.002–0.12 lg/ml) and 1 lg/ml (range, 0.12–1 lg/ml), respectively.
Figure 2 shows the measured concentrations of tebipenem in plasma (a) and middle ear effusion (b), as well as the sim- ulation curves based on the mean pharmacokinetic parameters with respect to 20 pediatric patients from whom blood and middle ear effusion were collected. The kp–m and km–p were estimated to be 0.68 (h-1) and 1.62 (h-1), respectively. The pharmacokinetic analysis using the blood specimens afforded
the following parameters: 5.3 ± 1.6 lg/ml (mean ± SD) in Cmax in plasma; 0.6 ± 0.1 h in time to reach maximum Tmax in plasma; 0.5 ± 0.2 h in T1/2; and 7.9 ± 0.2 lg h/ml in AUC0–? in plasma. Similarly, the pharmacokinetic analysis using the middle ear effusion specimens afforded the follow- ing parameters: 1.2 ± 0.1 lg/ml in Cmax in middle ear effu- sion; 1.1 ± 0.2 h in Tmax; 0.8 ± 0.2 h in T1/2; and
2.8 ± 0.4 lg h/ml in AUC0–? in middle ear effusion. The ratios of Cmax and AUC0–? in middle ear effusion to those in plasma were 0.23 and 0.36, respectively.
Sixteen of 17 pediatric patients who were reexamined at the time of administration completion or on the next day thereof were assessed as ‘‘healed.’’ The results of the PK– PD analysis of tebipenem in plasma and middle ear effu- sion from 16 pediatric patients, who provided 22 clinical isolates, are shown in Figs. 3 and 4, respectively. The PK– PD parameters (the fAUC/MIC ratio, the fCmax/MIC ratio, and the %fT [ MIC) in plasma were 5.3, 1.2, and 5.8, respectively, in 1 ‘‘unhealed’’ pediatric patient; therefore, these values were lower than those found in ‘‘healed’’ pediatric patients. Similarly, the PK-PD parameters (the AUC/MIC ratio, the Cmax/MIC ratio, and the %T [ MIC) in middle ear effusion were 5.9, 1.0, and 2.5, respectively, in the patient; therefore, these values were also lower than those found in ‘‘healed’’ pediatric patients.
Discussion
A randomized double-blind controlled clinical trial of tebipenem pivoxil and cefditoren pivoxil in 204 pediatric patients with otitis media [9] revealed that there was no significant difference between tebipenem pivoxil 4 mg/kg b.i.d. and cefditoren pivoxil 6 mg/kg t.i.d. with respect to clinical efficacy rate (98.2 and 92.6 %, respectively) and recurrence rate (9.0 and 7.2 %, respectively) and that tebipenem pivoxil was superior to cefditoren pivoxil in eradication rate (98.2 and 80.3 %, respectively; p = 0.0016) on day 3 of administration. In general, T [ MIC is considered as a PK–PD parameter for b-lactams. In carbapenem antibiotics, a favorable clinical outcome can be predicted when a free antibiotic in plasma has a T [ MIC value C25 % [10]. However, a preclinical study using the mouse model of femoral infection indicated greater correlation of the bacteriological efficacy of teb- ipenem pivoxil with the AUC/MIC rather than with T [ MIC [5]. A population pharmacokinetic study in more than 200 pediatric patients [4] examined the phar- macokinetics of tebipenem, and a PK–PD study in 70 pediatric patients [6] examined its bacteriological effects and clarified that the PK–PD parameter that correlates most closely with the bacteriological effects of tebipenem pivoxil is the AUC/MIC. However, PK–PD analysis of the drug at the target site has never been made to date. The present study analyzed the pharmacokinetics of tebipenem in middle ear effusion and indicated that middle ear effusion concentrations of tebipenem reached 1.0 lg/ml or greater after the twice-a-day oral administration of tebipenem pivoxil 6 mg/kg. This result supports the fact that tebipenem pivoxil shows high clinical outcomes for AOM because the MIC90 value of tebipenem for the major pathogens of AOM in children including drug-resistant bacteria is B1.0 lg/ml.
Fig. 1 Pediatric patient disposition.
Fig. 2 Time-course changes in plasma (a) and middle ear effusion (b) concentrations of tebipenem after oral administration of tebipenem pivoxil 6 mg/kg in 20 pediatric patients.
Because of its anatomical peculiarity of being sur- rounded by bone tissue, the middle ear cavity is a site where antibiotics exhibit poor transfer. Oral b-lactams, e.g., cefixime and amoxicillin, have middle ear effusion-to-Cmax ratios of 0.20–0.40 whereas cefpodoxime proxetil and cefuroxime axetil have ratios of only 0.10–0.20 [11]. Fur- thermore, cefprozil, another b-lactam antibiotic for which the pharmacokinetic profile in middle ear effusions was examined, has been reported to exhibit good penetration into the effusion (middle ear effusion-to-Cmax ratio, 0.29; middle ear effusion–AUC0–? ratio, 0.28) [12]. The phar- macokinetic values of tebipenem in middle ear effusion (middle ear effusion-to-Cmax ratio, 0.23; middle ear effu- sion–AUC0–? ratio, 0.36) are not inferior to the values of the current study, affirming the good transfer of tebipenem from the plasma into middle ear effusions. Therefore, tebipenem pivoxil was indicated to be a drug with good transfer. The results from the present clinical study indicate that the high healing rate of acute otitis media by tebipenem pivoxil is attributed not only to its potent anti- bacterial activity for the pathogens of respiratory diseases, including drug-resistant bacteria [1, 2], but also to the middle ear effusion concentration of tebipenem, which exceeds its MIC as a result of good transfer from plasma. In the present study, the PK–PD analysis was made considering the bacterial strains originating from naso- pharyngeal swab as putative pathogens because (1) bacteria do not grow in the culture medium when an antibiotic is present in the middle ear effusion and (2) middle ear effusion of a volume required for PK–PD analyses after oral administration of an antibiotic cannot be collected when collecting a middle ear effusion before administra- tion. The assessment procedures used in the present study are considered appropriate because AOM is established when resident flora in the nasopharynx enter the middle ear cavity through the eustachian tube [13]. The PK–PD analysis based on the pharmacokinetics of tebipenem in middle ear effusion revealed only one ‘‘unhealed’’ pediatric patient, which impeded the calculation of the target value. However, all patients for whom the drug was effective clinically and bacteriologically had an AUC/MIC ratio of C6, a Cmax/MIC ratio of C1.1, and a %T [ MIC of C6.
Fig. 3 Relationships between PK–PD parameters of tebipenem in plasma and clinical outcomes after oral administration of tebipenem pivoxil 6 mg/kg in 16 patients who provided 22 clinical isolates.
Fig. 4 Relationships between PK–PD parameters of tebipenem in middle ear effusion and the clinical outcomes after oral administration of tebipenem pivoxil 6 mg/kg in 16 patients who provided 22 clinical isolates.
The ‘‘unhealed’’ patient had presented with b-lactamase- producing ampicillin-resistant H. influenzae for which tebipenem had an MIC of 1 lg/ml. In contrast, two other pediatric patients in whom tebipenem had the MIC value for H. influenzae were healed. The ‘‘unhealed’’ pediatric patient was 12 months of age and was concurrently afflicted with acute rhinosinusitis; in this patient, rhinovirus had been detected at birth. The rhinopharyngeal cavity becomes the reservoir for bacterial otitis media, and viral infection triggers the penetration of bacteria into the middle ear cavity. When presenting with rhinosinusitis as a con- current disease, it is essential to appropriately perform nasal aspiration and nebulization in infants and younger children who cannot blow their nose.
Regarding AOM caused by S. pneumoniae, the con- centration of tebipenem in middle ear effusion (1.2 lg/ml) was much higher than its MIC of B0.12 lg/ml for the pathogen, probably explaining the 100 % healing rate (8/8) in the present study. Regarding AOM caused by H. influ- enzae, on the other hand, tebipenem pivoxil was effective for as many as 92.9 % (13/14) of the patients, presumably because its middle ear effusion concentrations exceed its MIC value. However, special caution should be paid to ampicillin-resistant clinical strains for some of which tebipenem has shown an MIC of C2 lg/ml.
The package insert of tebipenem pivoxil states the recommended dosage for children is 4 mg/kg of body weight twice daily, with allowable increases to the maximum dose of 6 mg/kg of body weight twice daily as required. Therefore, the maximum dose should be considered for pediatric patients who are at risk for the aggravation or prolongation of otitis media caused by resistant bacteria (e.g., BLNAR), who are less than 2 years old, who are under group nursing, who have received at least one anti- biotic, who are concurrently affected by rhinosinusitis, and who have a history of otitis media [14]. Indeed, the regi- men employed in the present study was successful and supports such a therapeutic approach.
In conclusion, the good transfer of tebipenem into the effusion corroborated the known high rate of clinical effi- cacy of tebipenem pivoxil for patients with AOM and the low incidence of recurrence. The results from the present study suggested positive correlations between plasma and middle ear effusion concentrations of tebipenem and between the middle ear effusion concentrations of tebipe- nem and the clinical effects of tebipenem pivoxil. Further study is required to validate the relationship between the AUC/MIC and the healing rate of tebipenem pivoxil in pediatric patients with AOM.
Acknowledgments The author is deeply grateful to Dr. Kimiko Ubukata, Kitasato University, for the isolation and culture of bacteria and for measurement of antibacterial activity, and to Dr. Nobuo Sato, Meiji Seika Pharma Co., Ltd., for his help with pharmacokinetic analyses. The present study was funded by Meiji Seika Pharma Co., Ltd. to cover part of the laboratory tests.
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