The 'Mechanism of Resistance Service' or MRS, which was established at Bristol Laboratories in July 1977 and continued through July 1979, has provided information to more than 300 hospitals in the United States and 11 other countries. The object has been to assist participating institutions that want to monitor the extent and nature of aminoglycoside resistance in their respective bacterial populations. Results show that of 1349 resistant isolates studied, about 90% were resistant to kanamycin and gentamicin, 67% to tobramycin, and 35% to amikacin. Almost all amikacin-resistant strains were cross-resistant with the other aminoglycosides. About 30% of the 1349 strains were susceptible to amikacin only. A total of 494 aminoglycoside modifying enzymes were detected in 577 isolates examined for their presence. Kanamycin's activity was apparently affected by 434 of these, gentamicin's by 291, tobramycin's by 282, and amikacin's by only 41 [all AAC(6′) from Gram-negative organisms]. Thus, no new enzymic mechanism of resistance for amikacin was detected in this study. The vast majority of the resistant organisms which failed to produce enzymes were found to have an impaired ability to transport aminoglycosides intracellularly. Isolates having this defect were generally resistant to all 4 aminoglycosides. As had been found in earlier studies, this mechanism was responsible for more than 90% of the amikacin resistance observed. In an effort to determine what effect intensive amikacin usage in a clinical setting would have on resistance levels to that antibiotic as well as to those of gentamicin and tobramycin, 5 prospective surveillance studies are being conducted. The level of resistance to each of these aminoglycosides was monitored during a minimum 3 month baseline phase during which average amikacin usage was 14·6% of total aminoglycosides used. Amikacin was then to be instituted as the first line aminoglycoside for a period of at least one year (average usage for the 5 hospitals during the study periods reported here was 82·4% No significant change in the amikacin resistance level (initially 1·1–3·5%) occurred in any of the 5 hospitals studied during the amikacin phase which has thus far ranged from 7 to 33 months. In 3 of the 5 hospitals, resistance levels to gentamicin showed a statistically significant decrease during the amikacin usage phase as compared to the baseline phase. Tobramycin resistance levels fell off significantly in 2 of the 3 hospitals reporting susceptibility data for this antibiotic. Le "Service de Mécanisme de la Résistance" (Mechanism of Resistance Service or MRS) qui a été créé par les Laboratoires BRISTOL en juillet 1977 et dont l'activité s'est poursuivie jusqu'en juillet 1979 a donné des informations concernant plus de 300 hôpitaux aux Etats Unis et dans 11 autres pays. Son objectif était d'aider les différents participants à suivre la nature et la fréquence de la résistance aux aminoglycosides dans leurs populations bactériennes respectives. Les résultats ont montré que sur les 1349 germes résistants qui ont été isolés, environ 90% étaient résistants a la Kanamycine et la Gentamicine, 67% a la Tobramycine et 35% à l'Amikacine. Presque toutes les souches résistantes à l'Amikacine présentaient une résistance croisée avec les autres aminoglycosides. Environ 30% des 1349 souches étaient sensibles seulement à l'Amikacine. Un total de 494 enzymes a été retrouvé chez les 577 germes chez lesquels la presence d'enzymes inactivant les aminoglycosides avait été recherchée. L'activité de la Kanamycine avait été supprimée par 434 enzymes, celle de la Gentamicine par 291, celle de la Tobramycine par 282 et celle de l'Amikacine par seulement 41 enzymes (dans tous les cas il s'agissait d'A.A.C. -6' de germes gram négatif). Ainsi aucun nouveau mécanisme de résistance à l'Amikacrnc n'a été mis en evidence dans cette étude. La majeure partie des germes résistants, qui ne produisait pas d'enzymes inactivants, présentait une diminution de leur capacité de transport intra-cellulaire des aminoglycosides. Lors d'études préalables il a été montré quece dernier mécanisme était responsable de plus de 90% de la résistance a l'Amikacine. Dans le but de determiner quelle pouvait être la consequence d'une utilisation large de l'Amikacine en clinique sur le niveau de résistance a cet antibiotique ainsi que sur celui de la Gentamicine et de la Tobramycine, 5 études prospectives de surveillance ont été entreprises. Le pourcentage de résistance à chacun de ces aminoglycosides a été soigneusement étudié pendant une période initiale d'un minimum de 3 mois durant lesquels la moyenne d'utilisation de l'Amikacine représentait 14, 6% du total des aminoglycosides prescrits. L'Amikacine a été alors utilisée comme le seul aminoglycoside pendant une période d'au moms I an (la moyenne d'utilisation dans les 5 h ôpitaux durant la période d'étude rapportée dans cette communication était de 82, 4%). Aucune augmentation significative du pourcentage de résistance a l'Amikacine (initialement 1, 1% à 3, 5%) n'a été observée dans aucun des 5 h ôpitaux la période d'utilisation de l'Amikacine qui est comprise, à l'heure actuelle, entre 7 et 33 mois. Dans 3 des 5 h ôpitaux le niveau de résistance a la Gentamicine a été réduit de facon statistiquement significative pendant la période d'utilisation de l'Amikacine, par rapport à la période initiale de traitement. Le pourcentage de résistance a la Tobramycine a diminué de façon nette dans les 3 h ôpitaux dans lesquels il existait des données concemant la sensibilityé a la Tobramycine.
It is well known that the composition of the assay medium greatly affects the antimicrobial activity of aminoglycoside antibiotics. A similar response has now been observed with certain penicillins and cephalosporins. In the case of these compounds, this effect is apparently governed by the chemical nature of the penicillin 6- and cephalosporin 7-side chains. In comparison with their activity in Nutrient Broth, the activity of some of the β-lactam antibiotics that have a weakly basic or basic group in their side chain was reduced as much as 40-fold in one or more of the following media: Mueller-Hinton, Trypticase soy, antibiotic assay, and heart infusion broths. In contrast, the assay medium had no effect on the activity of those compounds possessing an acidic or a nonionizable function in their side chain. The extent to which medium influences the antibacterial activity was also dependent upon the assay method and the organism, the effect being more pronounced in broth dilution than in agar dilution tests and occurring more frequently with gram-negative than with gram-positive organisms.
Summary Production and isolation methods of a new antitumor agent obtained from a Streptomyces culture are described. This water-soluble amorphous solid, which has been named actinogan, is insoluble in organic solvents and can be precipitated by acetone. It has a high molecular weight and by hydrolysis yields carbohydrate and amino acid residues. Isolation was accomplished by using Sarcoma 180 tumor inhibition as an assay, since the agent failed to demonstrate significant in vitro activity against bacteria, yeast, or protozoa and had only limited cytotoxicity for mammalian cells.
BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.
We explored the antibacterial activity of phosphanilic acid (P), an analog of sulfanilic acid, alone and in combination with trimethoprim (T; TP, 1:5) with sulfamethoxazole (S) and co-trimoxazole, the combination of this sulfonamide with trimethoprim (TS, 1:5) as the reference. P resembled S in spectrum but, in addition, had significant activity against Pseudomonas aeruginosa. The overall frequency and degree of synergism with TP were lower than with co-trimoxazole. P, like S, was strongly affected by changes in inoculum size and was not bactericidal. P was well absorbed parenterally but not orally in mice. Despite low (but prolonged) blood levels, P, given orally to mice, was effective in treating infections caused by P. aeruginosa. However, against most experimental infections the therapeutic effectiveness of P, as well as that of TP, administered either intramuscularly or orally was unimpressive. Based on in vivo data, the therapeutic application of P or TP would appear to be limited.
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