Critical evaluation of amdinocillin disk susceptibility tests correlated with agar dilution tests. (49/94)

Tests with 10-micrograms amdinocillin disks were performed in parallel with agar dilution tests and three different ranges of inoculum density. A resistance breakpoint of less than or equal to 13 mm and an intermediate category of 14 to 16 mm are recommended. Susceptible strains provided zones greater than or equal to 17 mm in diameter, but many appeared to be resistant by the agar dilution methods if the inoculum exceeded 10(4) CFU per spot.  (+info)

Penicillin binding proteins: role in initiation of murein synthesis in Escherichia coli. (50/94)

The consequences of the specific inhibition of penicillin binding proteins (Pbps) by beta-lactam antibiotics immediately before resumption of active growth in Escherichia coli suggest that inhibition of murein biosynthesis does not prevent the earlier steps of the initiation of cell growth in mass. The activity of Pbp 2 is apparently critical for the initiation of murein biosynthesis. Provided that Pbp 2 remains active, the other Pbps (1a, 1b, 3, 4, 5, and 6) can be inhibited without any noticeable effect on the initial rate of incorporation of new precursors into macromolecular peptidoglycan. These precursors are, in addition, inserted with a high degree of cross-linkage.  (+info)

Pharmacokinetics of intravenous amdinocillin in healthy subjects and patients with renal insufficiency. (51/94)

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocillin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.  (+info)

Quaternary heterocyclylamino beta-lactams. II. The in vitro antibacterial properties of L-640,876, a new type of beta-lactam antibiotic. (52/94)

A new semisynthetic cephalosporin antibiotic designated 7-beta-(1-benzylpyridinium-4-yl)-amino-3-[( (1-methyl-1H-tetrazol-5-yl) thio]methyl)ceph-3-em-4-carboxylate (L-640,876) was compared for antibacterial activity in vitro with mecillinam, cefoxitin and cefotaxime. The antibacterial spectrum of L-640,876 and the effect of culture medium composition and inoculum size on activity are most similar to those of mecillinam. In some cases the inoculum effect on MICs correlated with instability of the compound to certain beta-lactamases and in others to the presence of ionized compounds such as sodium chloride in the medium. On balance, L-640,876 was superior to mecillinam in potency and breadth of spectrum.  (+info)

Quaternary heterocyclylamino beta-lactams. IV. Comparison of the in vivo antibacterial activities of L-640,876, mecillinam, cefoxitin and cefotaxime. (53/94)

The novel beta-lactam, L-640,876, exhibited excellent therapeutic activity when administered parenterally but not orally to mice infected with a variety of pathogenic bacteria. In this respect, the compound was as potent as cefotaxime against representative Gram-positive and Gram-negative organisms, in most cases, equal to or more potent than cefoxitin, and more effective than mecillinam. When administered subcutaneously to normal mice at dose levels ranging from 10 to 50 mg/kg, L-640,876 provided an adequate dose response, recovery of ca. 45% of biological activity in the urine, and excellent distribution at the highest dose level into liver, lung, kidney, heart muscle, but not brain.  (+info)

Effects of mecillinam and cefoxitin on growth, macromolecular synthesis, and penicillin-binding proteins in a variety of streptococci. (54/94)

Although some strains of streptococci seem to be virtually inert to mecillinam, the growth of other strains, notably certain viridans streptococci (Streptococcus mutans and Streptococcus sanguis) was inhibited by relatively low concentrations of the drug. Inhibition of the synthesis of peptidoglycan, RNA, protein, and DNA in two tolerant strains, S. mutans FA-1 and GS-5, was studied over a wide range of concentrations of mecillinam, benzylpenicillin, and cefoxitin. The responses of both strains to all three beta-lactams were very similar; that is, synthesis of insoluble peptidoglycan was most susceptible. Inhibition of peptidoglycan synthesis was followed rapidly and sequentially by substantial but less severe inhibitions of RNA and protein synthesis. Significant inhibition of DNA synthesis was not observed. Binding studies with [14C]benzylpenicillin alone or after preexposure of membrane preparations to benzylpenicillin, mecillinam, or cefoxitin suggest that reasonably selective binding of a beta-lactam antibiotic to one or two of the major penicillin-binding proteins (PBP 1 or PBP 4) of S. mutans GS-5 and FA-1 may be the initial step in the series of events that results in the inhibition of growth and in the inhibition of insoluble peptidoglycan assembly and of RNA and protein synthesis.  (+info)

Cluster of mrdA and mrdB genes responsible for the rod shape and mecillinam sensitivity of Escherichia coli. (55/94)

Two closely linked genes, mrdA and mrdB, located at ca. 14.2 min on the Escherichia coli chromosomal linkage map, seen to be responsible for the normal rod shape and mecillinam sensitivity of E. coli. The product of mrdA was concluded to be penicillin-binding protein 2, because mrdA mutations caused formation of thermosensitive penicillin-binding protein 2. The product of the mrdB gene is unknown. At 42 degrees, C, mutation in either of these genes caused formation of spherical cells and mecillinam resistance. Both mutations was recessive, and complementation, as detected in +-/-+ meroheterodiploids having the wild-type phenotype, provided strong evidence that the two mutations are in different complementation groups. P1 transduction suggested that the most plausible gene order is leuS-mrdA-mrdB-lip. The rodA mutation reported previously seems to be similar to the mrdB murations, but the identities of the two have not yet been proven.  (+info)

Control of cell septation by lateral wall extension in a pH-conditional morphology mutant of Klebsiella pneumoniae. (56/94)

The pH-conditional morphology mutant of Klebsiella pneumoniae strain MirM7 grows as cocci at pH 7 and as rods at pH 5.8. The mutant has a high-level mecillinam resistance (50% lethal dose greater than 200 micrograms/ml) in both forms. When broth cultures of the rod-shaped mutant were grown with 0.7 microgram of mecillinam per ml, cells assumed a round shape and continued to divided at a higher rate than the untreated control. A MirM7 rod-shaped revertant (MirA12), when treated with the same antibiotic concentration, changed to coccal shape and stopped dividing. The penicillin-binding proteins (PBPs) of strains MirA12 and MirM7 were analyzed. K. pneumoniae had six major PBPs quite similar to those of Escherichia coli. No differences were seen in the PBPs of MirM7 cocci and rods and MirA12 cells. In particular, PBP2 was found to be present and similar in MirM7 rods and cocci and MirA12 cells. We suggest that that in gram-negative rods, a control mechanism exists which prevents further septation in the absence of lateral cell wall elongation. The unique behavior of MirM7 is due to the fact that the control mechanism is not active in this strain. This model allows us to explain the preservation of shape in bacterial rods under various conditions of growth and the mechanism of bacterial killing by mecillinam.  (+info)