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.

Single-dose treatment of male patients with gonococcal urethritis using 2g spectinomycin: microbiological and clinical evaluations.

The microbiological and clinical efficacies of a single-dose treatment of 2g spectinomycin administered by intramuscular injection were studied in 365 male patients with gonococcal urethritis. A total of 210 patients (57.5%) could be evaluated, in 28 (13.3%) of whom Chlamydia trachomatis was detected in addition to Neisseria gonorrhoeae. A single dose of spectinomycin eradicated N. gonorrhoeae in 203 (96.7%) of the 210 patients. Among patients in whom N. gonorrhoeae was eradicated, pyuria and clinical symptoms, respectively, disappeared in 92.6% (162/175) and 98.9% (173/175) of patients without concomitant C. trachomatis and in 78.6% (22/28) and 71.4% (20/28) with C. trachomatis. Minimal inhibitory concentrations (MICs) were determined for four of seven N. gonorrhoeae strains isolated after spectinomycin treatment. MICs to spectinomycin for three of the four isolates were 16 microg/mL (defined as susceptible) and the MIC of the other isolate was 128 microg/mL, indicating resistance. The resistant isolate was a multidrug-resistant strain with resistance to ciprofloxacin, tetracycline, penicillin and cephalosporins, except for ceftriaxone. The results of this study indicate that a single-dose treatment using 2g spectinomycin is effective in treating patients with urethritis caused by N. gonorrhoeae, even in the era of multidrug-resistant N. gonorrhoeae.

The effects of lincomycin-spectinomycin and sulfamethoxazole-trimethoprim on hyaluronidase activities and sperm characteristics of rams.

The effects of lincomycin-spectinomycin and sulfamethoxazole-trimethoprim combinations on the hyaluronidase enzyme of serum and semen and on sperm characteristics in rams were determined. Thirthy-two Akkaraman rams were used. The rams were randomly divided into four groups. Group A and group B were determined as control groups of group C (lincomycin-spectinomycin) and D (sulfamethoxazole-trimethoprim), respectively. Combinations of lincomycin-spectinomycin and sulfamethoxazole-trimethoprim were administered at doses of 15 mg.kg(-1) intramuscularly and 12 mg.kg(-1) body weights orally, respectively. Blood and semen samples were collected at 4, 12, 24, 48, 72, 192 and 384 hr. Semen hyaluronidase activities of rams in group C increased significantly (p<0.001, <0.05) compared with the control group at 24 and 48 hr, respectively. Semen hyaluronidase activities in group D rams also increased significantly (p<0.001) in comparison with the control group at all times except 72 and 384 hr. Serum hyaluronidase activities increased significantly (p<0.01, <0.001) at 24 and 48 hr after treatment of lincomycin-spectinomycin. Additionally, significant (p<0.05, <0.001) increases were detected in the serum hyaluronidase activities of group D at 48 and 72 hr, respectively. No significant correlation was found between serum and semen hyaluronidase activities. Furthermore, significant increases (p<0.05) were observed in the percentages of motile sperm in the rams of group C and D compared with the control groups. The values of sperm concentration and total number of sperm in group C and D rams decreased significantly (p<0.001) in comparison with control groups. No significant correlations were found between the semen hyaluronidase activities and sperm characteristics. In conclusion, these findings show that the combinations of lincomycin-spectinomycin and sulfamethoxazole-trimethoprim do not have any harmful effects on hyaluronidase activities and sperm motility. However, the use of both antibiotic combinations in breeding rams during the ramming season is not advisable due to the decrease of sperm concentration.

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.

Human safety and pharmacokinetics of a single intramuscular dose of a novel spectinomycin analog, trospectomycin (U-63,366F).

In this study, local and systemic tolerance and pharmacokinetics of trospectomycin sulfate in human beings were evaluated for the first time. Trospectomycin sulfate (U-63,366F; trospectomycin) or sterile saline was administered to 96 healthy male volunteers in doses ranging from 0.25 ml (75 mg) to 3.3 ml (1,000 mg) in a single intramuscular injection in a double-blind, randomized design. Volunteers were screened to establish baseline vital signs and laboratory test values. Pain and tenderness at the injection site, which occurred at doses of 450 mg and above, were the most common side effects; they were mild in severity and transient. Adverse drug experiences reported by subjects included nausea, dizziness, light-headedness, diaphoresis, costal pain, and perioral numbness. The perioral numbness (paresthesia) experienced at doses of 750, 900, and 1,000 mg was probably drug related. No Clostridium difficile toxin was detected in fecal samples. Pharmacokinetic calculations based on data obtained by high-performance liquid chromatography showed that after a 1,000-mg intramuscular dose of trospectomycin (3.3 ml), the serum mean half-life was 1.85 h (1.70 to 2.02 h), mean area under the serum concentration-time curve was 140.2 micrograms.h/ml and was linear with dose, mean peak concentration was 28.3 micrograms/ml (20.4 to 34.7 micrograms/ml), mean time to maximum concentration was 71 min (30 to 120 min), and the elimination rate constant was 0.307 h-1. The elimination rate constant and half-life did not vary with dose. Little trospectomycin was detected in 2-day fecal collections. A few randomly occurring abnormal clinical laboratory test values and vital signs were observed. For the trospectomycin-treated group, creatinine phosphokinase increased substantially for 24 h after injection and then decrease through day 5, while serum glutamic oxalacetic transaminase and lactate dehydrogenase increased slightly.

Multiple-dose, double-blind, placebo controlled intravenous tolerance and pharmacokinetic study of trospectomycin sulfate (U-63, 366F) in healthy male volunteers.

Trospectomycin sulfate is a novel aminocyclitol antibiotic. This study evaluated the tolerance and the pharmacokinetics of multiple, intravenous doses of trospectomycin (TRO) in healthy male volunteers. Three groups of 10 volunteers were studied. Eight volunteers in each group were studied in a parallel design to receive trospectomycin (Group 1 = 250 mg, Group 2 = 500 mg, Group 3 = 750 mg) while 2 volunteers received placebo (normal saline). Drug doses were administered in 30 ml volumes over 30 min every 8 h for 7 days (i.e. 21 total doses). Evaluations of vital signs, side effects, and safety laboratory tests were made at regular intervals during the study. The most frequent medical events observed in the volunteers receiving trospectomycin were perioral/facial paresthesias (54%), pain at the i.v. infusion site (46%), dizziness/lightheadedness (58%), and GI symptoms (38%). A statistically significant dose response relationship was observed for the incidence of perioral/facial paresthesias and pain at the i.v. infusion site (i.e., increased incidence with increased dose). All the medical events were mild or moderate in severity and reversible following drug discontinuation. In the 500 and 750 mg trospectomycin groups, standing systolic blood pressure decreased significantly with the first dose of study drug. Elevated levels of SGPT were observed in 9 volunteers (1 in placebo, 3 in 250 mg, 1 in 500 mg, and 4 in 750 mg dose groups). This study demonstrates that multiple intravenous trospectomycin doses up to 750 mg are reasonably well tolerated in healthy male volunteers. The concentration of trospectomycin in serum, measured with a sensitive HPLC assay, was less than 3 mcg/ml at 8 h postinfusion for all dose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and pharmacokinetics of intravenously administered trospectomycin sulfate.

Local and systemic tolerance and drug pharmacokinetics were evaluated after a single intravenous infusion of 75 to 1,000 mg of trospectomycin or placebo in 96 healthy volunteers. No clinically significant changes, trends, or abnormalities were observed in the vital signs, electrocardiograms, or laboratory test results; however, there were some statistically significant dose effects or dose-by-time interactions on some of the measures. Mild, transient, local reactions at the infusion site were reported by 20% of the trospectomycin-treated and 22% of the placebo-treated subjects. No irritation of the surrounding tissue was noted when extravasation occurred. Mild, transient, perioral-facial numbness, which was probably drug-related, was the most commonly reported systemic adverse drug experience, occurring in 17 of 64 trospectomycin-treated subjects, but only at doses of 600 mg and above. Pharmacokinetic analyses showed that after a 1,000-mg intravenous dose of trospectomycin, the mean serum half-life was 2.18 hr, the mean area under the curve (AUC) was 157.0 hr x micrograms/ml, the mean maximum concentration (Cmax) was 82.4 micrograms/ml, the mean time to maximum concentration was 25.0 min, and the elimination rate (Ke) was 0.33 hr-1. The Ke and half-life did not vary with dose, and both Cmax and AUC showed a strong linear trend. From 48% to 62% of the dose was excreted in the urine during the first 48 hours after infusion. Under the conditions of this study, intravenous trospectomycin was well tolerated by human subjects at single doses up to and including 1,000 mg.

Systemic anaphylaxis caused by parenteral spectinomycin.

Spectinomycin is commonly used for the treatment of uncomplicated gonorrhea, and is considered to be a safe drug. We have described a case of anaphylaxis characterized by peripheral vascular collapse after intramuscular administration of spectinomycin.

Cross-sensitivity within the neomycin group of antibiotics.

Neomycin sensitive patients were tested for hypersensitivity to kanamycin, gentamycin, tobramycin, spectinomycin and to the new, not yet registered sisomycin and netilmicin. Cross-sensitivity occured in a considerable part of the patients, except for spectinomycin, the structure of which is basically different from that of the other aminoglycosides tested. The common occurence of cross-sensitivity between neomycin and other aminoglycoside antibiotics shows that it is possible to predict cross-sensitivity between a new drug and an old sensitizing one before clinical reactions from the new drug have occured. Such an investigation should be performed before adopting new antibiotics.

National gonorrhea therapy monitoring study: adverse drug reactions.

The Center for Disease Control and cooperating clinics monitored adverse drug reactions in 6,969 patients who were treated for suspected uncomplicated gonorrhea with one of the four 1972 United States Public Health Service (USPHS) recommended regimens and returned for reexamination. Of those patients receiving the aqueous procaine penicillin G (APPG)-probenecid regimen, 2.0% had at least one adverse reaction and 0.18% experienced procaine reactions. No life-threatening reactions occurred. The overall reaction rates for the ampicillin-probenecid, tetracycline and spectinomycin regimens were 0.62%, 5.9%, and 0.61%, respectively. Our findings document the relative safety of the USPHS recommended regimens.

Spectinomycin - experimental investigations on possible side-effects.

Experimental investigations were performed to elaborate the immunogenic and anaphylactoid properties of spectinomycin. In guinea-pigs, no allergy against spectinomycin could be elicited. Furthermore, the absence of immunologic cross-reactions between spectinomycin and penicillin could be confirmed. The anaphylactoid activity of spectinomycin was found to be of very low order. No mast cell degranulating action could be observed. The data collected in this study permit the statement that - as far as acute unwanted actions of antibiotics are concerned - spectinomycin is an extremely safe drug.

Drugs five years later. Spectinomycin.

A single intramuscular injection of 0.2 g of spectinomycin hydrochloride is highly effective for the treatment of uncomplicated anogenital infections with Neisseria gonorrhoeae. Spectinomycin hydrochloride is indicated for uncomplicated anogenital gonococcal infections in men and women who cannot receive penicillin or probenecid, and is the drug of choice for the retreatment of patients with uncomplicated anogenital gonococcal infection who have not responded to other antibiotics. A single dose of spectinomycin does not appear to be reliably effective in the treatment of gonococcal pharyngitis. Preliminary reports indicate that multiple-dose schedules of spectinomycin will prove to be effective in gonococcal pelvic inflammatory disease and disseminated gonococcal infection. In the dosage used for gonococcal infections, spectinomycin has little effect on infection with Treponema pallidum. Evaluation of this antibiotic against other microorganisms suggests little utility for this agent in conditions other than gonococcal infections.

[Spectinomycin. Indications and undesirable effects]. / Spectinomycin. Indikationen und unerwünschte Wirkungen

Modern chemotherapy postulates highly active drugs without unwanted side effects. In the treatment of gonorrhea spectinomycin meets even the strictest requirements: maximal obtainable cure rates, no masking of concomitant syphilitic infections, and excellent tolerance. In animal experiments no sensitizing effect of spectinomycin was found even when maximation procedures were applied. Anaphylactoid activity of spectinomycin is low, as has been documented by personal investigational series.