tebipenem and Bacterial-Infections

The carbapenems are beta-lactam antimicrobial agents with an exceptionally broad spectrum of activity. Older carbapenems, such as imipenem, were often susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and required co-administration with a DHP-1 inhibitor such as cilastatin. Later additions to the class such as meropenem, ertapenem and doripenem demonstrated increased stability to DHP-1 and are administered without a DHP-1 inhibitor. Like all beta-lactam antimicrobial agents, carbapenems act by inhibiting bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs). Carbapenems are stable to most beta-lactamases including AmpC beta-lactamases and extended-spectrum beta-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within their PBPs, when they acquire metallo-beta-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins. Carbapenems (imipenem, meropenem, doripenem) possess broad-spectrum in vitro activity, which includes activity against many Gram-positive, Gram-negative and anaerobic bacteria; carbapenems lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Compared with imipenem, meropenem and doripenem, the spectrum of activity of ertapenem is more limited primarily because it lacks activity against Pseudomonas aeruginosa and Enterococcus spp. Imipenem, meropenem and doripenem have in vivo half lives of approximately 1 hour, while ertapenem has a half-life of approximately 4 hours making it suitable for once-daily administration. As with other beta-lactam antimicrobial agents, the most important pharmacodynamic parameter predicting in vivo efficacy is the time that the plasma drug concentration is maintained above the minimum inhibitory concentration (T>MIC). Imipenem/cilastatin and meropenem have been studied in comparative clinical trials establishing their efficacy in the treatment of a variety of infections including complicated intra-abdominal infections, skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia, complicated urinary tract infections, meningitis (meropenem only) and febrile neutropenia. The current role for imipenem/cilastatin and meropenem in therapy remains for use in moderate to severe nosocomial and p

Topics: Anti-Bacterial Agents; Bacterial Infections; beta-Lactams; Carbapenems; Doripenem; Ertapenem; Humans; Imipenem; Meropenem; Thienamycins

In a phase IIb clinical study (dose-finding test, 450 mg dosing group: 150 mg t.i.d., 500 mg dosing group: 250 mg b.i.d., 900 mg dosing group: 300 mg t.i.d.) of tebipenem pivoxil (TBPM-PI) for treatment of otolaryngological infections in adults, TBPM concentrations in the patient plasma were quantified. The primary pharmacokinetic parameters such as ka, kel, Vd/F and Tlag were estimated by the Bayesian method and then the secondary pharmacokinetic parameters such as tmax, Cmax, t1/2 and AUC were calculated. As for the patients whose primary parameters were not properly estimated by the Bayesian method, the secondary parameters were calculated by the trapezoidal method. The primary pharmacokinetic parameters obtained by the Bayesian method in 450 mg dosing group (150 mg t.i.d.), 500 mg dosing group (250 mg b.i.d.), and 900 mg dosing group (300 mg t.i.d.) were 5.64 +/- 2.76, 5.11 +/- 3.06 and 2.51 +/- 1.13 hr(-1) for ka, 1.75 +/- 0.25, 2.03 +/- 0.10 and 1.34 +/- 0.27 hr(-1) for kel, 17.62 +/- 5.09, 15.83 +/- 6.14 and 19.34 +/- 8.80 L for Vd/F, and 0.48 +/- 0.11, 0.38 +/- 0.03 and 0.39 +/- 0.26 hr for Tlag, respectively. The secondary parameters obtained by the Bayesian method and the trapezoidal method were 0.85 +/- 0.29, 0.81 +/- 0.33 and 1.18 +/- 1.53 hr for tmax, 5.08 +/- 2.05, 7.92 +/- 4.02 and 8.69 +/- 4.01 microg/ml for Cmax, 0.40 +/- 0.06, 0.34 +/- 0.01 and 0.54 +/- 0.10 hr for t1/2, 5.22 +/- 1.90, 7.93 +/- 4.04 and 13.62 +/- 6.29 microg x hr/ml for AUC after each dosing (AUC(0-8h) or AUC(0-12h)) and 15.65 +/- 5.70, 15.85 +/- 8.08 and 40.87+/- 18.87 microg x hr/ml for AUC(0-24h), respectively. As shown in the above, Cmax and AUC after each dosing were increased with a rise in the dose level, and AUC(0-24h) was increased with a rise in the total dose level per day. Regardless of the dosage, tmax was about 0.8-1.2 hr and t1/2 was about 0.3-0.5 hr, showing almost constant values. Changes in the regimen and dosage did not influence the pharmacokinetic properties of TBPM-PI. Pharmacokinetics of TBPM-PI in adult patients with otolaryngological infection were similar to those in healthy subjects.

Topics: Adult; Bacterial Infections; Carbapenems; Dose-Response Relationship, Drug; Female; Humans; Male; Otorhinolaryngologic Diseases

We conducted a double-blind intergroup comparative study investigating the efficacy, safety and PK-PD analysis of the new oral carbapenem antibacterial drug tebipenem pivoxil (TBPM-PI) for the treatment of otolaryngological infections in adults to establish the recommended clinical dosage. The primary endpoint was the clinical effect of a 7-day oral administration of TBPM-PI to subjects with confirmed cases of infection by any of the 5 major bacterial species causative for otolaryngological infections (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, and Haemophilus influenzae) assigned to three groups set according to the TBPM-PI dosage, namely, a 450 mg group (150 mg t.i.d), a 500 mg group (250 mg b.i.d), and a 900 mg group (300 mg t.i.d). 1. Clinical efficacy: At the end of administration or at discontinuation, the efficacy rate for the 112 subjects in the efficacy analysis set was 72.1% (31/43 subjects) in the 450 mg group, 88.6% (31/35 subjects) in the 500 mg group, and 85.3% (29/34 subjects) in the 900 mg group. Both the 500 mg and 900 mg groups showed a high efficacy rate of over 80%. 2. Bacteriological efficacy: The disappearance rate of the pre-administration causative bacteria (5 major bacterial species) at the end of administration (at discontinuation), it was 92.2% (47/51 strains) in the 450 mg group, 94.7% (36/38 strains) in the 500 mg group, and 91.7% (33/36 strains) in the 900 mg group. All the groups showed a high disappearance rate, with no large differences among them. All strains of S. pneumoniae, including PRSP, as well as those of S. pyogenes and M. catarrhalis disappeared. The overall disappearance rate of H. influenzae was 78.6%, namely, 76.9% in the 450 mg group, 100% in the 500 mg group, and 66.7% in the 900 mg group, showing differences among the groups. 3. PK-PD: The PK-PD analysis was executed in 124 strains isolated from 111 subjects in which the plasma TBPM concentration and the MIC of causative organism were measured. The target value of the PK-PD parameter was examined from the relation between PK-PD parameter and bacteriological efficacy. The presumed target value of AUCf/MIC was 10-20, Cmaxf/MIC was 4. On the other hand, a clear relation was not found between T>MIC and the bacteriological efficacy. 4.. The incidence of adverse reactions related to symptoms and signs was 28.8% (21/73 subjects) in the 450 mg group, 35.8% (24/67 subjects) in the 500mg group, and 30.6% (22/72 subjects) in the 900 mg group. The incidence of abnormal changes in laboratory test values was 8.2% (6/73 subjects) in the 450 mg group, 9.2% (6/65 subjects) in the 500 mg group, and 9.9% (7/71 subjects) in the 900 mg group. There were no differences in either of these categories among the groups, and the incidence was considered not to be correlated with dose. Based on the above, we considered that TBPM-PI at doses of 250 mg b.i.d (500 mg/day) promises high clinical usefulness for the treatment of otolaryngological infections in adults.

Topics: Administration, Oral; Adult; Aged; Bacteria; Bacterial Infections; Carbapenems; Drug Resistance, Microbial; Female; Humans; Male; Middle Aged; Otorhinolaryngologic Diseases; Treatment Outcome; Young Adult

We conducted the post-marketing surveillance of tebipenem pivoxil (Orapeneme fine granules 10% for pediatric), an oral carbapenem antibacterial agent, to investigate changes in bacterial susceptibility against tebipenem (TBPM). Bacterial strains used in this surveillance were methicillin-susceptible Staphylococcus aureus (MSSA: 303 strains), Streptococcus pneumoniae (554 strains), other Streptococcus spp. (242 strains: including Streptococcus pyogenes 133 strains), Moraxella catarrhalis (306 strains) and Haemophilus influenzae (506 strains) isolated from pediatric patients in 15 medical facilities in Japan between April 2010 and March 2015. Investigation was conducted three times (April 2010-March 2011, April 2012-March 2013 and April 2014-March 2015), and in any of these investigation periods, there were a large number of isolates from infants in terms of the frequency of isolates by age. The MIC90s of TBPM against MSSA, S. pneumoniae, other Streptococcus spp., M. catarrhalis and H. influenzae in these investigations were 0.015-0.03, 0.06, 0.008-0.015 (0.002 for S. pyogenes), 0.03 and 0.5-1 μg/mL, respectively, which were less than 2-fold, and a remarkable increase in MIC90 was not shown. On the other hand, the MIC50s of carbapenems including TBPM and penicillins against S. pneumoniae decreased to 1/4-1/8 during the investigation periods, and decreased gPRSP*¹ (48.7% - 26.1%) and increased gPISP (2x)*² (24.1% -+ 46.8%) were suggested to be involved in these changes in susceptibility. In S. pneumoniae, a decrease of macrolides-resistant strains due to mefA*³ (38.5% - 18.8%) and an increase of macrolides-resistant strains due to ermB*⁴ (41.7% - 62.4%) were noted. In H. influenzae, the frequencies of gBLNAR*⁵ and β-lactamase-producing strains were about 60-70% and 7-9%, respectively, and a remarkable change in susceptibility was not shown. As a result of investigations in the susceptibility of clinical isolates collected from pediatric patients as post-marketing surveillance, there was no decrease in TBPM susceptibility noted.

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Infections; Carbapenems; Child; Child, Preschool; Genotype; Humans; Infant; Microbial Sensitivity Tests; Mutation

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Carbapenems; Cephalosporins; China; Community-Acquired Infections; Humans; Microbial Sensitivity Tests; Respiratory Tract Infections