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Neisseria gonorrhoeae resistant to high levels of spectinomycin (more than 2,048 microng/ml), were isolated from specimens obtained from a patient with urethritis. The bacterial resistance to spectinomycin is probably due to ribosomal changes that are a result of a chromosomal mutation. If spectinomycin fails to cure gonorrhea, spectinomycin resistance should be considered.
Alterations in the ribosomes of sucrose-dependent spectinomycin-resistant (Sucd-Spcr) mutants of Escherichia coli were studied. Subunit exchange experiments showed that 30S subunits were responsible for the resistance of ribosomes to spectinomycin in all Sucd-Spcr mutants tested. Proteins of 30S ribosomes were analyzed by carboxymethyl cellulose column chromatography based on their elution positions. Mutants YM22 and YM93 had an altered 30S ribosomal protein component, S5, and mutant YM50 had an altered protein, S4. Although a shift of elution position was not detected for all the 30S ribosomal proteins from mutant YM101, the amount of protein S3 was appreciably lowered in the isolated 30S subunits. A partial reconstitution experiment with protein S3 prepared from both the wild-type strain and YM101 revealed that the mutant had altered protein S3 which is responsible for the spectinomycin resistance. These alterations in 30S subunits are discussed in relation to the interaction between ribosomes and the cytoplasmic membrane.
Ribosomal protein S5 was isolated from wild type Bacillus subtilis ATCC 6633 and from a spectinomycin resistant mutant (BSPC 111) derived from spectinomycin sensitive to resistance is accomtrypsin and all the tryptic peptides were isolated by column- and paper-chromatography. By comparative amino acid analyses of the peptides, it was demonstrated that the S5 from the mutant differs from the wild type S5 by a replacement of one amino acid, namely lysine by isoleucine in the peptide T9. The results are compared with E. coli spectinomycin resistant mutants.
A selective high-performance liquid chromatographic (HPLC) method with ultraviolet-visible (UV-VIS) detection was developed to measure therapeutic concentrations of spectinomycin in turkey plasma. Treatment of plasma samples with 3% trifluoroacetic acid in acetonitrile facilitated spectinomycin extraction and protein precipitation. After centrifugation, the stable derivatization reagent, 2,4-dinitrophenyl-hydrazine, was added to an aliquot of the supernatant, and the mixture was incubated for 30 min at 70 degrees C. Excess reagent was quenched with acetone and additional heating. The resulting derivative, a proposed spectinomycin-hydrazone, was separated from other compounds by reversed-phase HPLC during a short gradient run. The absorbance of the effluent was monitored spectrophotometrically with the UV-VIS detector set at 205 nm. The detector response was linear through the range of interest, 2-100 micrograms/ml.
The susceptibilities to spectinomycin of 303 recent urinary tract isolates were determined and compared to the susceptibilities of those strains to ampicillin, tetracycline, and gentamicin. Based on minimal inhibitory concentrations, 84% of Escherichia coli, Klebsiella, and Enterobacter, 31% of other Enterobacteriaceae, 7% of Staphylococcus aureus and Streptococcus (including enterococci), and 0% of Pseudomonas aeruginosa were susceptible to concentrations of spectinomycin that are easily surpassed in serum (</=32 mug/ml); 90% of all organisms tested other than P. aeruginosa were susceptible to concentrations that are easily surpassed in urine (</=128 mug/ml). Spectinomycin was active against more isolates than either ampicillin or tetracycline but against fewer isolates than gentamicin. Disk diffusion susceptibility tests did not reliably distinguish susceptible from resistant isolates with any of the four antibiotics studied.
110 patients with uncomplicated gonococcal urethritis were treated with 2 g spectinomycin (Trobicin) intramuscularly. Seventy-five patients were available for follow-up and there was only one treatment failure, giving a cure rate of 98-6%. Of the 99 gonococcal isolates, 59 were sensitive to 5 microng/ml of spectinomycin or less and 40 were sensitive to 10 microng/ml. In a small sample of patients 2 g spectinomycin intramuscularly produced a serum concentration averaging 100 microng/ml after one hour.
Sixty-three heterosexual men were successfully treated with a single injection of spectinomycin hydrochloride 2 g for urethral infections with Neisseria gonorrhoeae. Chlamydia trachomatis was recovered from the urethra of 11 of these men both before and after treatment. In six men, the organism was isolated after but not before treatment. No isolates were obtained from the remaining men either before or after treatment. All 17 of the men who yielded C. trachomatis developed post-gonococcal urethritis. Eight of 46 men from whom no isolate was obtained in their cultures developed post-gonococcal urethritis. Seventeen of 50 women successfully treated with spectinomycin for cervical infections with N. gonorrhoeae yielded isolates of C. trachomatis both before and after treatment. The organism was isolated from five women before but not after treatment, and from four women after but not before treatment. In 24 women culture for C. trachomatis was negative both before and after treatment. Spectinomycin hydrochloride in the dosage used rarely eliminated C. trachomatis from the genital tract of either men or women; in this respect it resembled two other drugs commonly used for the treatment of gonorrhoea-pencillin and ampicillin.
Spectinomycin inhibits the formation and causes dissociation of performed specific cell-free initiation complexes prepared with the trinucleotide A-U-G or R17 phage RNA, fmet-RNAF and either 30S ribosomal subunits or 70S ribosomes. Both the initiation factor and the Mg2+-induced processes are subject to inhibition by spectinomycin. The only exception is the Mg2+-induced 70S initiation system formed with A-U-G which is stimulated by spectinomycin.
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.
A spontaneously arising nuclear mutation, ss-1, has been identified in Chlamydomonas reinhardtii that decreases both streptomycin and spectinomycin resistance levels about 10-fold after its introduction into all wild-type, streptomycin-resistant and spectinomycin-resistant strains examined. The mutations for resistance map to nuclear and uniparentally inherited (chloroplast) loci. In contrast, no modification of erythromycin resistance was detected after introducing ss-1 into wild-type strains or into strains carrying nuclear or uniparentally inherited erythromycin-resistance mutations. We suggest that ss-1 affects the small subunit of the chloroplast ribosome because others have shown that streptomycin and spectinomycin resistance in C. reinhardtii are associated with this subunit, whereas erythromycin resistance is associated with the large subunit. ss-1 shows no linkage with the nuclear locus for streptomycin resistance.
The sensitivity and reproducibility of the radioenzymatic adenylylating assay for spectinomycin were improved by modifications of the assay procedure and by partial purification of the enzyme. The presence of Bacillus subtilis ribosomes or S-150 fraction in the enzymatic reaction mixture interfered with the ability to measure spectinomycin by this method.
A mutant of Escherichia coli has been isolated which exhibits partial suppression of spectinomycin resistance. The site of mutation is in the streptomycin (strA) region and is closely linked to the spcA gene. However, this gene, which we propose to call mod, is phenotypically distinguishable from both the neomycin-kanamycin (nek) and the ribosomal ambiguity gene (ram). The relative gene order is mod spcA strA. In a cell-free protein synthesizing system, altered ribosomes appear to be responsible for the suppression of spectinomycin resistance caused by mod.
Spectinomycin dependence in Bacillus subtilis involves two mutations, one conferring drug resistance and the other producing a requirement for spectinomycin for growth.
Of 104 male and nine female patients with uncomplicated acute gonorrhoea who were treated with spectinomycin (males 2 g., females 4 g.), two patients (one male and one female) were considered to be treatment failures. No conclusions can be drawn from the small numbers of female patients investigated. Of the 104 male patients, 93 were followed for 2 weeks or more, giving a failure rate of 1-1 per cent. The drug was well tolerated. Sensitivity tests were carried out on 44 strains of N. gonorrhoeae; 42 strains were sensitive to 2-5 mug./ml. spectinomycin and all strains were sensitive to 5 mug./ml.
Three replicate trials were conducted with broiler male chicks to test the therapeutic efficacy of doxycycline, chlortetracycline and lincomycin-spectinomycin in water against an artifically induced Escherichia coli infection. Mortality, lesion scores (heart, liver and air sac), and performance data were the criteria in evaluating therapeutic efficacy of these drugs. Results indicated the therapeutic efficacy of doxycycline was greater than chlortetracycline and lincomycin-spectinomycin.
7-Epi-spectinomycin (9) and 7-epi-4(R)-dihydrospectinomycin (10) have been prepared and their structure firmly established by proton magnetic resonance. Both of these spectinomycin analogs are devoid of antibiotic activity.
Haemophilus vaginalis is highly sensitive to oleandomycin. The MIC ranged from 0.035 to 0.15 mug/ml. The sensitivity of H. vaginalis to spectinomycin was 2.5-5.0 mug/ml. The sensitivity of H. vaginalis to spectinomycin is 3-4 times higher than that of Neisseria gonorrhoeae. A favourable effect in the treatment of vaginitis caused by H. vaginalis could thus be expected.
Results following treatment of acute gonorrhea with aqueous penicillin combined with probenecid and spectinomycin hydrochloride (2.0 g) are compared and found to be statistically equivalent. Therefore, if a patient is allergic to penicillin, spectinomycin hydrochloride can be regarded as a valuable alternative. The results appear to be the same whether probenecid is administered simultaneously or 1/2-2 h before penicillin. It is advisable to control all patients one week after therapy. A second control after 2 weeks for men and after the next menstruation for women is highly desirable. If the patient fails to respond to treatment, not only an increase in the antibiotic dose, but also prolongation of therapy by administering the same dose on 3 consecutive days, is effective.