Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and intrapulmonary aerosol administration in mice.

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. Intrapulmonary aerosol (IPA) administration of lead spectinamide 1599 has previously been shown to be more efficacious than subcutaneous (SC) administration at comparable doses. The objective of the current study was to characterize the disposition of 1599 in plasma and lungs in mice in order to provide a potential rationale for the observed efficacy differences. 200 mg/kg of 1599 was administered to healthy BALB/c mice by SC injection or by IPA delivery. Plasma and major organs were collected at specified time points until 8 h after dosing. Drug concentrations were measured by LC-MS/MS and analyzed by noncompartmental pharmacokinetic analysis. 1599 demonstrated rapid absorption into plasma after IPA and SC administration, resulting in very similar plasma exposure for both routes. In contrast, drug exposure in the lungs was 48 times higher following IPA as compared to SC administration, which is highly desirable as the lungs are the main site of infection in pulmonary TB. The higher local exposure in the lungs is likely the basis for the increased efficacy after IPA compared to SC administration. Overall, this study supports the pulmonary route as a potential pathway for the treatment of tuberculosis with 1599.

Dynamic time-kill curve characterization of spectinamide antibiotics 1445 and 1599 for the treatment of tuberculosis.

Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration-dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is T > MIC for 1445, but fCmax/AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post-antibiotic effect: 15.7 h for 1445 compared the 133 h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds.

Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections.

Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.

Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

Antibiotic penetration of experimental intra-abdominal abscesses.

Intra-abdominal abscess is seldom adequately treated by systemic antibiotics alone and often requires surgical or computed tomography-guided drainage for resolution. Abscess penetration of six currently used antibiotics was examined in a murine intra-abdominal abscess model. Ampicillin/sulbactam, cefmetazole, clindamycin, and trospectomycin penetrated intra-abdominal abscesses to a greater degree than cefoxitin and ceftriaxone. Abscess pus antibiotic levels were not significantly higher after multiple doses than after a single dose. Pus antibiotic levels below the MIC90 for Bacteroides and E. coli within intra-abdominal abscess were observed for most antibiotics with the doses used in this study. Selection of antibiotics with a greater ability to penetrate abscess may be important in optimally treating patients with abdominal infection.

Efficacy of 250 mg trospectomycin sulfate i.m. vs. 250 mg ceftriaxone i.m. for treatment of uncomplicated gonorrhea.

BACKGROUND AND OBJECTIVES: Due to the steadily progressive development of resistance to the drugs used for treatment, Neisseria gonorrhoeae remains a medical concern. Trospectomycin sulfate is a 6' propyl analogue of spectinomycin with potent activity against penicillin sensitive and resistant strains of N. gonorrhoeae. GOAL OF THIS STUDY: To compare the efficacy of 250 mg trospectomycin sulfate i.m. versus 250 mg ceftriaxone i.m. for single dose therapy for men and women with uncomplicated gonorrhea. STUDY DESIGN: Dual-center, randomized comparative trial. RESULTS: Among evaluable male patients with urethral gonorrhea, 36 of 40 (90%, 95% confidence interval [95%CI] 76%-97%) who were treated with trospectomycin sulfate were cured, and 22 of 22 patients (100%, [85%-100%]) treated with ceftriaxone were cured. Among evaluable female patients with cervical gonorrhea all were cured following trospectomycin sulfate (23 of 23) and following ceftriaxone therapy (13 of 13). The cure rates for pharyngeal gonorrhea were 67% (8 of 12 patients, 35%-90%) for trospectomycin sulfate therapy, and 100% (2 of 2) with ceftriaxone therapy. CONCLUSIONS: Trospectomycin sulfate, 250 mg i.m., is effective, and well tolerated. However, for treatment of uncomplicated genital and pharyngeal gonorrhea, it is not as reliable for therapy as other recommended regimens.

Treatment of gonococcal infections with a single 250 mg intramuscular injection of trospectomycin sulphate vs ceftriaxone sodium.

Trospectomycin sulphate is a new, more potent analog of spectinomycin, which is active in vitro against penicillin-sensitive and penicillin-resistant strains of Neisseria gonorrhoeae. This study was designed to determine the bacteriologic and clinical efficacy as well as safety of a single intramuscularly administered 250 mg dose of trospectomycin sulphate in the treatment of uncomplicated gonorrhoea (cervical, urethral, pharyngeal and anal). Ceftriaxone sodium was used as a comparator antibiotic in a single 250 mg intramuscular dose. Seventy-four patients (36 women and 38 men) were evaluable in the trospectomycin treated group and 40 patients (22 women and 18 men) in the ceftriaxone treated group. The overall bacteriologic cure rate was 98.6% (73/74) for trospectomycin and 95% (38/40) for ceftriaxone. Bacteriologic failures were observed among women 1/36 (2.8%) treated with trospectomycin and 2/22 (9.1%) treated with ceftriaxone. The overall clinical success rate (clinically cured plus clinically improved) was 90.5% for trospectomycin and 100% for ceftriaxone. Adverse events were reported rarely in both groups. Less than 10% of patients complained of pain and/or tenderness at the injection site for both drugs; one patient developed a generalized, pruritic rash which occurred three days after administration of trospectomycin and resolved within six days. In conclusion, a single dose of 250 mg i.m. trospectomycin appears to be at least as effective and safe as a single dose of ceftriaxone in the treatment of uncomplicated gonorrhoea.