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PubMed1976

[Ototoxicity of spectinomycin (author's transl)].

Spectinomycin is an aminocyclitol antibiotic, but different in chemical structure from other aminocyclitol antibiotics such as streptomycin, kanamycin and gentamicin. Spectinomycin clinically has been proven to be highly effective in the intramuscular single-dose treatment of gonorrhea. According to NOVAK et al. (1974), all evidence from pharmacological and clinical efficacy studies to date indicates that spectinomycin is free from ototoxic effects at the dose levels recommended for single-dose treatment of gonorrhea (2 or 4 g) or repeated i.m. or i.v. doses, 8g/day. The present experimental study has been made to evaluate the ontoxocic effects of spectinomycin in Hartley strain guinea pigs given i.m. a single-high dose (800 mg/kg or 1,600 mg/kg) and repeated-slightly higher dose (80 mg/kg or 160 mg/kg daily for 4 weeks) respectively. Differential frequency pinna reflex test in frequency range from 20 KHz to 500 Hz revealed that no animals showed disappearance of pinna reflex in the frequencies tested. Histologic examination in serial celloidin sections of the cochlea and vestibulum disclosed that a few animals given a single-high dose of spectinomycin (800 mg/kg or 1,600 mg/kg) and repeated-slightly higher dose or spectinomycin (80 mg/kg daily for 4 weeks) respectively showed limited mild damage of outer hair cells in the spiral organ and of hair cells in the vestibular organ. There were histologically a few focal necrosis in the liver and scattered interstitial cell infiltration around the proximal convoluted tubules which are lined with regenerated epithelial cells in some animals given the single-high dose (800 mg/kg or 1,600 mg/kg) or repeated-slightly higher dose (80 mg/kg or 160 mg/kg daily for 4 weeks) of spectinomycin. Positive correlation between the extent of the hair cell damage and the injury of the liver and kidney was not confirmed. The present study suggests that administration of spectinomycin at the dose levels recommended for single-dose treatment of gonorrhea (2 or 4 g) most probably is free from ototoxic effect.

Animals↗

PubMed1970

Enzymatic Adenylylation of Streptomycin and Spectinomycin by R-Factor-Resistant Escherichia coli.

A resistance (R) factor- containing strain of Escherichia coli which is known to inactivate streptomycin by adenylylation has been shown to be spectinomycin resistant. An osmotic shockate of this strain catalyzes the formation of the biologically inactive spectinomycin adenylate, in which the adenylyl residue is probably attached to a d-threo methylamino alcohol moiety of spectinomycin. Both the streptomycin and spectinomycin adenylylating activities show the same temperature inactivation profile, and both are present in a protein fraction purified for the streptomycin inactivating enzyme. Mutants obtained from this strain which were sensitive to either spectinomycin or streptomycin were shown to lack both enzymatic activities when tested in vitro. Revertants of these mutants selected for recovery of either streptomycin resistance or spectinomycin resistance regain both activities. Therefore, we conclude that the inactivation of the two drugs is catalyzed by the same enzyme. Examination of a number of R factor-carrying strains has shown that those strains which are resistant to streptomycin and spectinomycin contain the adenylylating enzyme, whereas strains resistant to streptomycin but sensitive to spectinomycin inactivate streptomycin by phosphorylation.

Journal Article↗

PubMed1988

In vitro antibacterial activity of trospectomycin (U-63366F), a novel spectinomycin analog.

Trospectomycin (U-63366F) is a novel spectinomycin analog with broad-spectrum antibacterial activity. The in vitro activity of this analog was compared with that of spectinomycin and other reference antibiotics against 411 clinical isolates of aerobic and anaerobic bacteria. MICs were determined by agar or broth dilution methods. The stability of trospectomycin in the presence of an enzyme extract derived from spectinomycin-resistant Escherichia coli was determined. Trospectomycin was more active than spectinomycin (4- to 32-fold) against strains of numerous bacterial species, including staphylococci, streptococci, Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, Proteus species, Bacteroides species, Clostridium difficile, Clostridium species, and Chlamydia trachomatis. Trospectomycin demonstrated a moderate level of activity (comparable to that of spectinomycin) for most species of the family Enterobacteriaceae tested and was generally cross resistant with spectinomycin. Trospectomycin was susceptible to inactivation by crude enzyme preparations from spectinomycin-inactivating strains of E. coli. Trospectomycin inhibited a variety of clinically important organisms, including agents of sexually transmitted diseases and pelvic inflammatory disease. Clinical studies with this novel aminocyclitol antibiotic are in progress.

Anti-Bacterial Agents↗

PubMed1987

Spectinomycin resistance and associated DNA amplification in Streptomyces achromogenes subsp. rubradiris.

Streptomyces achromogenes subsp. rubradiris plated at low density on 1,000 micrograms of spectinomycin per ml initially produces slow-growing, bald colonies from which arise, in a spatially and temporally random fashion, foci of rapidly growing aerial mycelium-forming cells whose DNA contains an approximately 200- to 300-fold amplification of an 8-kilobase (kb) sequence. This sequence was cloned in Escherichia coli on pBR322 and physically characterized. It was separately cloned also in Streptomyces lividans as a BglII fragment and shown to impart high-level resistance to spectinomycin in an orientation-independent manner when present in either the high-copy-number vector pIJ702 or the unit-copy-number vector pIJ943. A spectinomycin resistance determinant was shown to reside on a 1.7-kb SphI-BglII subfragment. Analysis of Southern blots of restriction enzyme digests of wild-type S. achromogenes DNA probed with the labeled 8-kb DNA sequence resulted in the identification and subsequent cloning in S. lividans of a 10.4-kb BamHI fragment which probably includes the complete 8.8-kb amplifiable unit of DNA. This unit is present in wild-type S. achromogenes and in the initially slow-growing, bald colonies arising on 1,000 micrograms of spectinomycin per ml as a single copy. It carries two 0.8-kb direct repeats at its termini as well as the spectinomycin resistance determinant close to one of these termini. About 5% of protoplast regenerants from wild-type S. achromogenes and 77% of protoplast regenerants from the rapidly growing strains lost both the ability to grow on spectinomycin at 10 micrograms/ml and the sequences that hybridize with the 8-kb probe DNA. The 1.7-kb Bg/II-SphI resistance fragment, when introduced via the vector pIJ702 into an S. achromogenes strain sensitive to 10 microgram of spectinomycin per ml, permitted its vigorous growth on 1,000 micrograms of the antibiotic per ml.

Chromosome Mapping↗

PubMed1985

Testing sensitivity of Neisseria gonorrhoeae to spectinomycin.

A concentration of 16 mg/l spectinomycin incorporated in agar gave the best discrimination between Neisseria gonorrhoeae sensitive and resistant to spectinomycin. This method was compared with spectinomycin sensitivity testing with 25 micrograms or 100 micrograms discs. Both methods agreed fully for 197 spectinomycin sensitive and three spectinomycin resistant gonococci. The agar incorporation "breakpoint" concentration technique failed to detect a small spectinomycin resistant population in a fourth isolate, which was detected by disc testing. It may be possible to predict the emergence of spectinomycin resistance among strains of N gonorrhoeae.

Microbial Sensitivity Tests↗

PubMed1976

[In vitro antibacterial effects of spectinomycin and penicillin G on Neisseria gonorrhoeae singly and in combination (author's transl)].

The antibacterial effects of spectinomycin and penicillin G on clinical isolates of Neisseria gonorrhoeae were studied. The concentrations of penicillin G at which the isolates showed drug sensitivity ranged widely from 0.011 to 6.25 mug/ml. Some of the isolates were resistant to penicillin G. Sensitivity to spectinomycin was observed at the drug concentrations ranging from 3.13 to 12.5 mug/ml. About 60% of the isolates were sensitive to 6.25 mug/ml of spectinomycin, and those isolates which were resistant to penicillin G showed good sensitivity to spectinomycin. No correlation in sensitivity was noted between the two drugs. Tests for their bactericidal activities on bouillon media revealed that the addition of spectinomycin at the concentration of 12.5 mug/ml or over produced a marked bactericidal effect in a short time while penicillin G exhibited a bactericidal or bacteriostatic effect depending upon the concentration used. A synergistic effect of a penicillin and an aminoglycoside antibiotic was observed in these isolates of N. gonorrhoea as was in the isolates of Pseudomonas aeruginosa. Where penicillin G and spectinomycin were used in combination, a simultaneous addition of both the drugs produced the most marked synergistic effect. Morphology of N. gonorrhoeae cells exposed to either of these drugs was examined under a scanning electron microscope. Exposure to spectinomycin at the level of 6.25 mug/ml resulted in almost no morphological change. At 6.25 mug/ml of the drug, however, a roughened cell surface, a bleb-like structure or a state suggesting the loosening of such a bleb-like structure was noted. The addition of penicillin G at 0.19 mug/ml led to an impairment of cell division at one hour of exposure and to cell swelling and lysis with further exposure. At 1.19 mug/ml of the drug, these processes of cell swelling and lysis took place early.

Drug Combinations↗

PubMed2000

Spectinomycin inhibits the self-splicing of the group 1 intron RNA.

Effects of the aminoglycoside spectinomycin on the self-splicing of primary transcripts of the phage T4 thymidylate synthase gene (td) have been investigated. The kinetic analysis demonstrated that spectinomycin acts as a mixed noncompetitive inhibitor for the td intron RNA with a K(i) of 7.2 mM. Increasing the spectinomycin concentration raised the K(m) values with the corresponding decrease of V(max) and k(cat) values. The specificity of the splicing inhibition by spectinomycin is due to changes in both K(m) and k(cat). The splicing inhibition by spectinomycin is dependent on pH changes and Mg(2+) concentration, indicating electrostatic interactions with the intron RNA. It has been proposed that the key structural features in spectinomycin responsible for the inhibition of splicing may be the hydroxyl groups on the antibiotic.

Guanosine Triphosphate↗

PubMed1977

A spectinomycin dependent mutant of Escherichia coli.

A mutant of Escherichia coli B has been isolated which shows a novel phenotype of spectinomycin dependence. The mutant, termed RD, needs spectinomycin to grow at temperatures of 37 degrees or below; it is unable to grow at 42 degrees in either the presence or absence of spectinomycin. Secondary mutants which grow well in the absence of spectinomycin can be isolated spontaneously at a frequency of about 10(-6). Two-dimensional gel electrophoresis of ribosomal proteins from 25 of these revertants showed that two revertants had an alteration in S4; one other showed an alteration in L5, and one showed an apparent absence of L1. Mutant RD itself had an altered less basic S5, which was maintained in all the revertants that were checked. Genetic analysis indicated that RD was a double mutant: one mutation, which alone conferred a spectinomycin resistant phenotype on the strain, was located in the strA region of the E. coli chromosome and was represented by the mutation in S5. The other mutation, which conferred the dependence on spectinomycin, mapped close to the rif locus.

Escherichia coli↗

PubMed2006

Development of a hydrophilic interaction chromatography-mass spectrometry assay for spectinomycin and lincomycin in liquid hog manure supernatant and run-off from cropland.

A specific and sensitive analytical method was developed to extract and quantify spectinomycin and lincomycin in liquid hog manure supernatant and simulated rainfall run-off from manure-treated cropland. Sample extracts were prepared using solid-phase extraction (SPE) employing a weak cation-exchange resin (Oasis WCX) for extraction of spectinomycin. An Oasis HLB cartridge was used for extraction of lincomycin. Hydrophilic interaction chromatography (HILIC) was used to obtain the necessary separation of the two antibiotics from interfering compounds and to provide baseline separation. Analytes were detected using atmospheric pressure chemical ionization tandem mass spectrometry. Extraction recoveries were 77% for lincomycin and 84% for spectinomycin in liquid hog manure supernatant, and 89% for lincomycin and 95% for spectinomycin in run-off water. The corresponding limits of quantitation were 6.0 and 0.040 microg l(-1) for spectinomycin and lincomycin, respectively, in liquid hog manure supernatant and 0.2 and 0.008 microg l(-1) for spectinomycin and lincomycin, respectively, in run-off from manure treated cropland. The method is suitable for monitoring the environmental fate and transport of these two antibiotics in both liquid hog manure and agricultural field run-off.

Animals↗

PubMed2000

K(+) and Mg(2+) ions promote the self-splicing of the td intron RNA inhibited by spectinomycin.

The effects of Mg(2+) and K(+) ions on the self-splicing inhibition of the td (thymidylate synthase gene) intron RNA by spectinomycin were investigated. The maximum splicing activity occurred at 20 mM KCl. The K(m) and V(max) values for GTP in the presence of 5 mM Mg(2+) are 2.25 microM and 0.55 min(-1), whereas those for GTP both in the presence of 5 mM Mg(2+) and 5 mM K(+) are 1.23 microM and 0. 46 min(-1), respectively. Spectinomycin at 10 mM concentration inhibited the splicing by about 10%, but at 20 mM concentration, the splicing rate was inhibited by about 63%. The splicing inhibition by the low concentration of spectinomycin was overcome markedly as the concentration of Mg(2+) ion was raised. At 30 mM spectinomycin, however, the splicing inhibition was not significantly affected by increasing the concentration of Mg(2+). A similar activation of the splicing rate was observed as the concentration of K(+) ion was increased. The concentration of K(+) ion required for the normal recovery of the splicing was much higher than that of Mg(2+) ion. Unlike Mg(2+) ion, 30 mM K(+) ion effectively alleviated the splicing inhibition by spectinomycin at its high concentration. The results indicate that K(+) and Mg(2+) ions may show mechanistically different interactions with spectinomycin in the self-splicing reaction of the td intron RNA.

Animals↗

PubMed1977

Spectinomycin versus tetracycline for the treatment of gonorrhea.

Spectinomycin and tetracycline are alternative drugs to penicillin in the treatment of gonorrhea. To compare the efficacy of these agents and their propensity to select resistant gonococci, we treated 4043 patients randomly with either 2 or 4 g of spectinomycin once or 9 g of oral tetracycline for four days. Minimum cure rate for anogenital gonorrhea was 94 per cent with either drug. Oropharyngeal infection responded poorly to spectinomycin in men, with failure of therapy in six of 11. Postgonococcal urethritis in men was less common after tetracycline than after spectinomycin (P less than 0.005). Spectinomycin failure was not related to drug resistance. Tetracycline failure correlated with resistance (P less than 0.0002); one fifth of the isolates resistant to 1.0 mug per milliter of tetracycline were not eradicated. For several reasons, including the appearance of beta-lactamase-producing gonococci, it is no longer clear that penicillin G is the "drug of choice" for gonorrhea. Spectinomycin and tetracycline are equally acceptable alternatives, each with distinct advantages and disadvantages.

Administration, Oral↗

PubMedDate not supplied

Evaluation of spectinomycin and gentamicin in the treatment of hospitalized patients with resistant urinary tract infections.

Spectinomycin hydrochloride 140 mg/kg/day and gentamicin 3 mg/kg/day were evaluated in the treatment of 50 hospitalized patients with urinary tract infections. Seven patients (28%) in the spectinomycin group had positive urine cultures after 72 hours of therapy due to initial resistance of the organism (5 isolates) or development of resistance to spectinomycin (2 isolates). Response to gentamicin therapy was uniformly satisfactory. Complications of spectinomycin therapy included pain and induration at the injection site (11 patients) and elevated serum creatinine values (2 patients). Ototoxicity was noted in three patients given gentamicin. Peak serum concentrations of spectinomycin (range 55-157 microgram/ml) and gentamicin (range 2.8--8.5 microgram/ml) showed marked interpatient variation. Spectinomycin appears to be of limited value in the treatment of urinary tract infections caused by gram-negative bacilli.

Adult↗

PubMedDate not supplied

Treatment of chancroid with a single dose of spectinomycin.

Fifty patients with lesions characteristic of chancroid were enrolled in an open-label prospective study to examine the efficacy of a single 2-gm dose of spectinomycin for treatment of chancroid. Only those patients (41 men; aged 18 to 49 years) with positive culture results for Haemophilus ducreyi were included in the analysis. Patients each received a single 2-gm dose of spectinomycin intramuscularly. The recovery process began on the third day of follow-up, as evidenced by the occurrence of epithelialization and a decrease in inflammation. By the seventh day after treatment, only one patient had ulcers; 40 patients experienced eradication of all ulcers (P less than 0.0001). The condition of nodes affected by infection also indicated efficacy of treatment (P less than 0.01); only one patient still had a swollen node by the fourteenth day after treatment. Of the 41 patients, 37 (90%) had negative culture results for H. ducreyi on the third day after treatment. Only 4 patients (10%) required a second dose of spectinomycin on the seventh day to affect a cure. Treatment with spectinomycin resulted in a 98% cure rate 14 days after treatment. The minimum inhibitory concentration (MIC) of spectinomycin was 1 microgram/mL to 3 micrograms/mL in the 15 strains studied. The drug was well tolerated and no adverse reactions were reported. It is concluded that a single 2-gm dose of spectinomycin is a safe and effective alternative drug for treatment of chancroid.

Adolescent↗

PubMed1976

Coordinated alterations in ribosomes and cytoplasmic membrane in sucrose-dependent, spectinomycin-resistant mutants of Escherichia coli.

Alterations in cytoplasmic membrane and ribosomes from sucrose-dependent spectinomycin-resistant (Sucd-Spcr) mutants of Escherichia coli, mutants that are resistant to spectinomycin in the presence of 20% sucrose but sensitive in the absence of sucrose, were studied. The protein composition of cytoplasmic membrane was analyzed by gel electrophoresis on polyacrylamide gel containing 8 M urea and 0.5% sodium dodecyl sulfate, which assured the reproducible separation of 28 protein bands. A major protein band, I-19, was missing in all cytoplasmic membrane preparations from 10 Sucd-Spcr mutants. Besides protein I-19, proteins I-13 and I-24 were missing in some mutants. On the other hand, the protein composition of cytoplasmic membrane from a sucrose-independent spectinomycin-resistant mutant was indistinguishable from that from the wild-type strain. The polypeptide synthetic activity of ribosomes from Sucd-Spcr mutants was resistant to spectinomycin. Studies on a revertant obtained from one of these mutants without any selection for sensitivity to spectinomycin revealed that a single mutation was responsible for both the ribosomal alteration, i.e., spectinomycin resistance, and the lack of protein I-19 in the cytoplasmic membrane. Studies on a transductant obtained with a Sucd-SPcr mutant as the donor also confirmed the single-mutation concept. It was concluded that in Sucd-SPcr mutants an alteration in the ribosomes caused the deletion of protein I-19 from cytoplasmic membrane.

Bacterial Proteins↗

PubMed1988

Single dose oral norfloxacin or intramuscular spectinomycin to treat gonorrhoea (PPNG and non-PPNG infections): analysis of efficacy and patient preference.

Norfloxacin, a new oral quinolone, was compared with intramuscular spectinomycin for treating culture proved gonorrhoea (caused by penicillinase producing strains of Neisseria gonorrhoeae (PPNG) and non-PPNG strains. A total of 547 infected men and women were randomly allocated to treatment with either single dose norfloxacin (800 mg by mouth) or spectinomycin (2 g intramuscularly). Patient preference for tablets or injections was noted at this visit. Patients returned four to eight days later for assessment of efficacy, safety, and preference. Of the 482 patients who attended follow up, all those treated with norfloxacin (94 infected with PPNG strains, 145 with non-PPNG strains) and all 82 infected with PPNG strains and treated with spectinomycin were cured. Of 161 infected with non-PPNG strains and treated with spectinomycin, 159 (99%) were cured. Side effects (headache, nausea, and sleepiness) occurred in three patients receiving norfloxacin and in 17 (16 pain at injection site, 1 giddiness) receiving spectinomycin. Most patients preferred tablets to injection both on day 1 (313 v 200) and at follow up (373 v 104). This study showed that norfloxacin was a highly effective alternative to spectinomycin, produced fewer side effects, and was the preferred mode of administration.

Administration, Oral↗

PubMed2002

Isolation of spectinomycin resistance mutations in the 16S rRNA of Salmonella enterica serovar Typhimurium and expression in Escherichia coli and Salmonella.

Two single-base mutations in 16S rRNA conferring high-level resistance to spectinomycin were isolated on a plasmid-borne copy of the rrnD operon from Salmonella enterica serovar Typhimurium. Neither of the mutations (C1066U and C1192U) had appreciable effects on cell growth, but each had differential effects on resistance to spectinomycin and fusidic acid. Both mutations also conferred resistance to spectinomycin in Escherichia coli strains containing deletions of all seven chromosomal rrn operons and expressing plasmid-encoded Salmonella rRNA exclusively. In contrast, when expressed in E. coli strains containing intact chromosomal rrn operons, the strains were sensitive to spectinomycin. However, chromosomal mutations arose that allowed expression of the rRNA-dependent spectinomycin resistance phenotype. It is proposed that in heterogeneous rRNA populations, the native E. coli rRNA out-competes the heterologous Salmonella rRNA for binding to ribosomal proteins, translation factors, or ribosome assembly, thus limiting entry of the antibiotic-resistant 30S subunits into the functioning ribosome pool.

Anti-Bacterial Agents↗

PubMedDate not supplied

Penicillin and spectinomycin in treatment of gonococcal urethritis.

In view of the recent discovery of penicillinase-producing strains of Neisseria gonorrhoeae in Zambia, the efficacies of single intramuscular doses of aqueous procaine penicillin G (4.8 x 10(6) units plus 1 g of oral probenecid) and 2 g of spectinomycin were evaluated in an open clinical trial of the treatment of acute gonococcal urethritis in men. The former regimen was given to 123 men; failure of treatment was observed in 9.1% of the 88 men followed for two weeks. Spectinomycin was given to 124 men; treatment failure occurred in 3.8% of the 104 men followed for two weeks. During the trial, 190 unselected isolates of N. gonorrhoeae were screened by rapid iodometric test, and two penicillinase-producing strains were detected. MICs of penicillin and spectinomycin were determined by the agar dilution method for 110 and 98 isolates, respectively. MICs of penicillin of greater than or equal to 0.125 micrograms/ml were observed with 78.2% of the strains, while 83.7% had MICs of spectinomycin of less than or equal to 15.0 micrograms/ml. It was suggested that penicillin be given routinely for treatment of gonorrhea in Zambia and that spectinomycin be reserved for treatment of gonococcal infections not cured by penicillin.

Acute Disease↗

PubMedDate not supplied

The neuromuscular blocking action of spectinomycin on the mouse hemidiaphragm preparation.

1. The mechanism of action of the muscle paralysing property of the antibiotic spectinomycin has been investigated on the isolated mouse phrenic nerve-hemidiaphragm preparation. 2. Spectinomycin produced a neuromuscular blockade that was poorly reversed by neostigmine (3 mumol/l) but well reversed by both calcium (5 mmol/l) and 3,4-diaminopyridine (0.1 mmol/l). 3. Intracellular techniques were used to record endplate potentials and miniature endplate potentials from hemidiaphragms paralysed by spectinomycin. Miniature endplate potentials were reduced both in frequency and in amplitude. The quantal content of the endplate potential during spectinomycin paralysis calculated by the method of variance was 14, a value similar to that found in preparations paralysed by the prejunctionally active magnesium. 4. Thus spectinomycin possesses weak neuromuscular blocking activity by a predominant action on acetylcholine release.

Action Potentials↗