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SUMMARY Interest in the evolution of gonococcal auxotrophy led to a study of 72 strains isolated between 1935 and 1948 from the urogenital tract (57 patients), the eye (two patients), and from disseminated gonococcal infections (11 patients and probably two others). Two cervical isolates with nutritional requirements for proline, arginine, histidine, and biotin were oxidasepositive, Gram-negative diplococci, but their identity as Neisseria gonorrhoeae was uncertain because they were atypically susceptible to colistin and did not produce acid in glucose media. The N gonorrhoeae strains were highly susceptible to 11 other antibacterial drugs but not to sulphadiazine. Defects of one or more pathways for the biosynthesis of methionine, proline, arginine, threonine, lysine, the branched-chain amino acids, hypoxanthine, and thiamine pyrophosphate were found in 39 of the 70 strains, including four isolated in the presulphanilamide era. Unexpectedly, methionine was required for the growth of 11 (21 %) of the 52 Danish strains and for 13 (72%) of 18 strains isolated in the USA. The Danish strains included 28 (54%) that did not require any of the compounds used for differentiating auxotypes, whereas this type was represented by only three (17%) of the USA strains. None of the gonococci required uracil or other pyrimidines. This suggests that the requirements for arginine, hypoxanthine, and uracil commonly found in recent isolates from disseminated gonococcal infections probably evolved after treatment with sulphonamide was replaced by penicillin.

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The line structure of Haemophilus vaginalis (Gardner and Dukes 1955) was compared with that of four, possibly related species (Butyribacterium rettgeri, Corynebacterium diphtheriae var. mitis, Lactobacillus acidophilus, Haemophilus influenzae) and an unrelated species, Neisseria haemolysans, which had shown a similar degree of Gram-variability as that of H. vaginalis. Although H. vaginalis was first described as a Gram-negative rod, its fine structure, particularly that of cell wall and septa, was more like that of Gram-positive organisms. Also N. haemolysans had a fine structure close to that of Gram-positive organisms, and its typical Gram-positive cell wall varied in. thickness from one cell to another.The study did not solve the problem of the classification of the so-called H. vaginalis, but the appearance of the few strains studied in the electron microscope suggests that it: should be included in Corynebacterium or Butyribacterium rather than in Lactobacillus.

Since the late thirties, physicians have been in a very fortunate position with regard to the therapy of gonorrhoea. At that time the sulphonamide drugs were discovered and produced a revolution in the treatment of gonorrhoea; when the incidence of resistant gonococcus strains became too high, penicillin came into the picture, closely followed by streptomycin and tetracycline. In addition, other antibiotics have a considerable effect on the gonococcus in vivo and in vitro (chloromycetin, erythromycin, oleandomycin, syntomycin, novobiocin, kanamycin, etc.); yet, in spite of the decreasing clinical effect and the increasing incidence of allergic response, the drug of choice has been and still is penicillin. Certain disadvantages exist for most of the other antibiotics, and they cannot be recommended, at least not for large-scale routine treatment or for use alone. Factors relevant in this connexion are: cost, method of application, toxicity, tendency to development of less sensitive or resistant strains, and selective effect on other bacteria such as the staphylococci and klebsiellae.It is well known that complete resistance to streptomycin develops very easily, and it was recently shown by Meyer-Rohn (1958) that gonococci can be made completely resistant to erythromycin and oleandomycin, and that some resistance to tetracycline can also be developed.In this paper the problems of sensitivity and treatment are considered mainly from the bacteriological point of view. The considerations are based upon work done at the Statens Seruminstitut in Copenhagen and it is not intended (to any great extent) to refer to other similar work. The gonococcus department of the Statens Seruminstitut in Copenhagen serves as a centre for the entire country, about 100,000 specimens being received each year; about 10-12 per cent. result in positive cultures, 80 per cent. being from women and 20 per cent. from men (10,000 to 12,000 positive cultures per year). PenicillinLate in 1955 four gonococcal strains were isolated from a case of uncomplicated gonorrhoea which was refractory to repeated "ordinary" penicillin treatment; all four strains showed a sensitivity to penicillin twenty times lower than usual. The lowered sensitivity persisted, and after the usual dose of penicillin the patient's serum showed levels similar to those commonly observed. This observation, together with the increasing use of oral penicillin, and the increasing number of allergic cases, made it desirable to review the sensitivity of gonococci to penicillin and to other possible antibiotics. In addition, a few reports were found from other countries, in which a change in the distribution of the in vitro concentrations necessary for complete in vitro inhibition was described.Preliminary testing by means of the tablet method of 300 strains isolated in 1956 showed that 10 per cent. of these strains were about twenty times less sensitive than usual.The department possessed a collection of freezedried strains, among which a high number had been isolated and dried befor...

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In a clinical trial of spiramycin, Schmidt, Niordson, Reyn, and Bentzon (1965) observed a positive correlation between the susceptibility of gonococcal strains in vitro to spiramycin and sodium penicillin G, and that the gonococcal strains from thirteen patients not cured by spiramycin were less sensitive to penicillin. Positive correlation could also be demonstrated between the inhibitory values of spiramycin and tetracycline for strains that were both resistant to streptomycin and less sensitive to penicillin. Reyn and Bentzon (1968) confirmed that a comparatively high degree of resistance to spiramycin in vitro was correlated with an increased resistance to penicillin. The correlation was most evident for strains that were resistant to streptomycin. Another peculiar feature observed was that of the fourteen strains with moderately decreased susceptibility to penicillin; seven were highly sensitive to spiramycin but at the same time completely resistant to streptomycin. Strains with moderately decreased susceptibility to penicillin were rarely found in that material, and it was suggested that they might represent a group with special genetic qualities. In contrast to the Danish results reported Durel, Roiron, and Nicod (1967) did not observe any correlation between the susceptibility to penicillin and spiramycin in a study of 302 gonococcal strains. In the present study, the material was supplemented by selected groups of strains with a view to further analysis of the relationships between the sensitivities of gonococcal strains to spiramycin and penicillin. Material and MethodsIn addition to the 173 gonococcal strains examined in the preceding paper mentioned above, 338 strains isolated during the years 1960-1968 were examined with penicillin (penicillin 0, Leo), streptomycin (dihydrostreptomycinum ®, Leo), tetracycline (tetracyclin 0, Lepetit), and spiramycin (rovamycin ®, May and Baker). The sensitivity to erythromycin ® (Abbott) was examined for 93 of the 338 new strains. Care was taken in selecting the supplementary material to include strains with varying degrees of decreased sensitivity to penicillin simultaneous with sensitivity to streptomycin. The whole series comprised 411 gonococcal strains covering a 1,000-fold range of sensitivity to penicillin; 279 of these were sensitive and 132 resistant to streptomycin. Except in the examination with erythromycin, the plate-dilution method described by Reyn and co-workers was used (Reyn, Korner, and Bentzon, 1958; Reyn, Bentzon, and Ericsson, 1963). The results were given in pg./ml. of 50 per cent. inhibitory concentrations (IC50-values). Strains with . 0-045 ,ug. sodium penicillin G per ml. were considered as being "less sensitive".The sensitivity to erythromycin was determined by a diffusion method using 20 hours' prediffusion (Thomsen, 1962).Five strains artificially made more resistant to penicillin by subculture at increasing concentrations of penicillin were examined in a special experiment. These strains were already less sensitive to penicillin and ...

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