Comparative in vitro activity of Bay k 4999 and piperacillin.
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Azlocillin↗
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Sensitivity testing and synergy.
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Azlocillin↗
Bacteriological antagonism between acylureidopenicillins and cephalosporins.
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Anti-Bacterial Agents↗
Mechanisms of beta-lactam resistance in British isolates of Pseudomonas aeruginosa.
The mechanisms of resistance to beta-lactam antibiotics in 191 isolates of Pseudomonas aeruginosa were examined. These represented the most resistant organisms of 1866 isolates collected during a national survey of antibiotic resistance in this species. One hundred and seventy-two isolates were selected because they were resistant to carbenicillin (MIC greater than 128 mg/L) and 19 because the MICs of cefotaxime were greater than the MICs of carbenicillin. Of the carbenicillin-resistant isolates, 35 produced plasmid-mediated beta-lactamases known to be active against carbenicillin and seven produced unusual beta-lactamases; in 131 strains, resistance could not be attributed to beta-lactamase production and was considered to be intrinsic. The unusual antibiogram in which the MIC of cefotaxime was greater than the MIC of carbenicillin was associated with overproduction of the chromosomally-determined Sabath and Abrahams ' beta-lactamase. Selection of strains with this last mechanism represents a novel resistance problem and one which may increase with increased use of newer antipseudomonal beta-lactams.
Anti-Bacterial Agents↗
Pharmacokinetics of Bay k 4999, a new broad-spectrum penicillin.
The pharmacokinetics of the broad-spectrum penicillin Bay k 4999 were studied in six healthy male volunteers. A 2-g dose was given by the intravenous route. The tissue penetration of the antibiotic was studied by both dermabrasion and blister techniques. A total of 26.4% of the drug was recovered in the urine in 24 h, 79% of this being excreted in the first 2 h. The elimination half-life in serum was 1.3 h. The dermabrasion levels of Bay k 4999 were generally similar to those in serum, but after 1 h the blister fluid levels of antibiotic were greater than those in serum. Different drug levels obtained by blister and dermabrasion techniques may be due to the different composition of the two fluids.
Adult↗
In vitro activity of furazlocillin (Bay k 4999) compared with those of mezlocillin, piperacillin, and standard beta-lactam antibiotics.
The activity of furazlocillin (Bay k 4999) was compared with those of mezlocillin, piperacillin, and standard beta-lactam antibiotics against a number of gram-positive and gram-negative organisms. These new expanded-spectrum penicillins were less active than penicillin G against most gram-positive organisms. Furazlocillin, mezlocillin, and piperacillin showed activity comparable to ampicillin and penicillin G against Haemophilus influenzae and penicillin-susceptible neisseriae, respectively. None of the drugs tested was effective against penicillin-resistant gonococci. The activity of furazlocillin was greater than that of mezlocillin, piperacillin, ampicillin, or carbenicillin against many Enterobacteriaceae. However, certain beta-lactam-resistant strains among these organisms were not highly susceptible to any of the three new penicillins. Furazlocillin was less active than piperacillin against Pseudomonas aeruginosa but was more active than carbenicillin or mezlocillin. Inoculum effects and discrepancies between minimal inhibitory concentrations and minimal bactericidal concentrations were observed with furazlocillin, mezlocillin, and piperacillin against several genera. The kinetics of bacterial killing by the new penicillins were often slow and incomplete over 24 h, especially in tests with Enterobacter and P. aeruginosa. Synergy was demonstrated between furazlocillin and aminoglycosides against a variety of gram-negative bacilli and Streptococcus faecalis.
Aminoglycosides↗
Penicillin-binding proteins in Clostridium perfringens.
The penicillin-binding proteins (PBPs) of Clostridium perfringens were studied. Six PBPs ranging in molecular weight from approximately 42,000 to 100,000 were detected in the cytoplasmic membrane. The relative affinities of the PBPs for 16 beta-lactam antibiotics were determined. Most of the drug saturated PBP 3 and 4 at concentrations equal to their minimal inhibitory concentrations, suggesting that these PBPs are the killing targets for beta-lactams. Mecillinam showed unique properties; it had a higher affinity for PBP 5 than for other PBPs, and it was the only agent tested which caused inhibition of growth without saturating PBP 4. Interestingly, all beta-lactam antibiotics tested induced filament formation despite having different binding patterns to the PBPs of C. perfringens.
Azlocillin↗
Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance.
Wild-type strains of Pseudomonas aeruginosa are more resistant to various beta-lactam antibiotics as well as other agents than most enteric bacteria. Although resistance to compounds of earlier generations is explained by the synergism between the outer membrane barrier and the inducible beta-lactamase, it was puzzling to see significant levels of resistance to compounds that do not act as inducers or are not hydrolyzed rapidly by the chromosomally encoded enzyme. This intrinsic-resistance phenotype becomes enhanced in those strains with the so-called intrinsic carbenicillin resistance. In the accompanying paper (X.-Z. Li, D. M. Livermore, and H. Nikaido, Antimicrob. Agents Chemother. 38:1732-1741, 1994), we showed that active efflux played a role in the resistance, to various non-beta-lactam agents, of P. aeruginosa strains in general and that the efflux was enhanced in intrinsically carbenicillin-resistant strains. We show in this paper that, in comparison with the drug-hypersusceptible mutant K799/61, less benzylpenicillin was accumulated in wild-type strains of P. aeruginosa and that the accumulation levels were even lower in intrinsically carbenicillin-resistant strains. Deenergization by the addition of a proton conductor increased the accumulation level to that expected for equilibration across the cytoplasmic membrane. In intrinsically carbenicillin-resistant isolates, there was no evidence that either nonspecific or specific permeation rates of beta-lactams across the outer membrane were lowered in comparison with those of the more susceptible isolates. Furthermore, these carbenicillin-resistant isolates were previously shown to have no alteration in the level or the inducibility of beta-lactamase and in the affinity of penicillin-binding proteins. These data together suggest the involvement of an active efflux mechanism also in the resistance to beta-lactams. Hydrophilic beta-lactams with more than one charged group did not cross the cytoplasmic membrane readily. Yet one such compound, ceftriaxone, appeared to be extruded from the cells of more-resistant strains, although with this compound effects of proton conductors could not be shown. We postulate that wild-type strains of P. aeruginosa pump out such hydrophilic beta-lactams either from the periplasm or from the outer leaflet of the lipid bilayer of the cytoplasmic membrane, in a manner analogous to that hypothesized for multidrug resistance protein of human cancer cells (M.M. Gottesman and I. Pastan, Annu. Rev. Biochem. 62:385-427, 1993).
Anti-Bacterial Agents↗
Evidence for involvement of penicillin-binding protein 3 in murein synthesis during septation but not during cell elongation.
Furazlocillin (1 microgram/ml) and piperacillin (5 microgram/ml) bound specifically to penicillin-binding protein 3 (PBP-3) and not to the other major PBPs in intact Escherichia coli cells. The effect of this specific binding to PBP-3 on murein synthesis of elongating and synchronously septating cells was investigated in two thermosensitive division mutants, E. coli BUG6 and E. coli JE10730, the latter possessing a thermolabile PBP-3. Synchronous cell division was induced by shifting the cultures from the nonpermissive temperature (42 degrees C) to 30 degrees C. Both [14C]diaminopimelic acid incorporation into murein of intact cells and [14C]N-acetylglucosamine incorporation into murein of cells permeabilized with ether was inhibited by an average of 42% in septating cells. In filaments growing at the nonpermissive temperature, we detected no inhibition and, frequently, a 10 to 15% stimulation of murein synthesis. The two drugs, at concentrations used in the above experiments, bound exclusively to PBP-3 both in elongating and septating intact cells and in ether-treated cells. These results support the hypothesis that PBP-3 activity is exclusively required for septal murein synthesis.
Azlocillin↗
Effects of furazlocillin, a beta-lactam antibiotic which binds selectively to penicillin-binding protein 3, on Escherichia coli mutants deficient in other penicillin-binding proteins.
Furazlocillin binds selectively to penicillin-binding protein 3 (PBP-3), prevents septation of Escherichia coli, and allows the cells to form long filaments without lysis. The effect of furazlocillin on the morphology, autolysis, and murein synthesis of E. coli mutants deficient in either PBP-1A, PBP-1Bs, or PBP-2 was studied. The results reveal that PBP-1A and PBP-1Bs functions are not equivalent since furazlocillin affects the morphology, autolysis, and murein synthesis of PBP1A- mutants quite differently from that of PBP-1Bs mutants. Different "PBP-2-" mutants were found to respond to furazlocillin in dramatically different ways: strain LS-1 cells formed elongated rods with a central bulge which eventually lysed, whereas SP6 cells formed stable "barbells" in which the two daughter cells were well separated but remained connected by a thick central region.
Azlocillin↗
Volume growth, murein synthesis, and murein cross-linkage during the division cycle of Escherichia coli PA3092.
Cells of Escherichia coli PA3092 were synchronized by centrifugal elutriation. The synchronously growing cells were double labeled with -3H or DL-[meso-2,6-14C]diaminopimelic acid (DAP) at different times. Cells incorporated [3H]DAP at a continuously increasing rate during their cycle, with a maximum occurring at about 30 min before division for trichloroacetic acid-precipitated cells (whole cells) and about 10 min before division for sodium dodecyl sulfate-treated cells (sacculi). This was in good agreement with the observed kinetics of volume growth under these conditions. Furazlocillin, which preferentially interacts with penicillin-binding protein 3, modified the pattern of incorporation of [3H]DAP. Electron microscopy indicated that furazlocillin did not inhibit the initiation of division but rather its completion. In addition, we measured the cross-linking of the murein inserted at different times during synchronous growth. The highest percentages were found to occur around division. At this same time, the cross-linking of old peptidoglycan was found to be decreased.
Azlocillin↗
Use of ureidopenicillins for selection of plasmid vector transformants in Pseudomonas aeruginosa and Pseudomonas putida.
Broad-host-range plasmids coding for beta-lactamase were successfully selected after transformation of Pseudomonas strains. Transformants of both Pseudomonas aeruginosa and Pseudomonas putida containing plasmid pRO1614 were isolated in media containing low concentrations of piperacillin. These strains were also susceptible to other ureidopenicillins. Similar selections of transformants with carbenicillin, ampicillin, or ticarcillin required high concentrations of antibiotics and yielded backgrounds of spontaneous resistant mutants.
Ampicillin↗
Interaction of FtsA and PBP3 proteins in the Escherichia coli septum.
Mutations in the ftsA gene of Escherichia coli conferred a higher resistance to lysis induced by penicillin or by a combination of cefsulodin and furazlocillin. The ftsA2 allele codes for an FtsA protein which is inactive at 42 degrees C but is able to regain its activity once it is transferred back to 30 degrees C; ftsA2 filaments formed at 42 degrees C in the presence of penicillin divided once the penicillin was removed and the temperature was lowered to 30 degrees C. Potential septation sites in the filaments of wild-type cells treated in the same way remained inactive. The binding of a radioactively labeled derivative of ampicillin to penicillin-binding protein 3 (PBP3) was significantly decreased in strain D-3, containing the mutant allele ftsA3, when the binding assay was performed at the restrictive temperature. A molecular species able to cross-react with an anti-PBP3 serum was nevertheless found to be present in the envelope of D-3 cells. These observations suggested that the FtsA protein, a protein with a structural and regulatory role in septation, and PBP3, a protein enzymatically active in the synthesis of murein for septation, interact with each other.
Alleles↗
Two distinct transpeptidation reactions during murein synthesis in Escherichia coli.
Murein synthesized in ether-permeabilized cells of Escherichia coli deficient in individual penicillin-binding proteins (PBPs) and in the presence of certain beta-lactam antibiotics was analyzed by high-pressure liquid chromatography separation of the muramidase split products. PBP 1b was found to to be the major murein synthesizing activity that was poorly compensated for by PBP 1a. A PBP 2 mutant as well as mecillinam-inhibited cells showed increased activity in the formation of oligomeric muropeptides as well as UDP-muramylpeptidyl-linked muropeptides, the reaction products of transpeptidation, bypassing the lipid intermediate. In contrast, penicillin G and furazlocillin severely inhibited these reactions but stimulated normal dimer production. It is concluded that two distinct transpeptidases exist in E. coli: one, highly sensitive to penicillin G and furazlocillin, catalyzes the formation of hyper-cross-linked muropeptides, and a second one, quite resistant to these antibiotics, synthesizes muropeptide dimers.
Amdinocillin↗
Partitioning of a mini-F plasmid into anucleate cells of the mukB null mutant.
The partition-proficient mini-F plasmid pXX325 was stably maintained in the mukB null mutant, which is defective in chromosome partitioning into the two daughter cells. In the null mutant, the plasmid was partitioned into both nucleate and anucleate daughter cells, independently of host chromosomes.
Azlocillin↗
FtsI and FtsW are localized to the septum in Escherichia coli.
The localization of FtsI (PBP3), a penicillin-binding protein specifically required for cell division in Escherichia coli, was investigated by immunofluorescence microscopy and found to localize to the septum. The localization of FtsI was not observed in ftsZ or ftsA mutants, indicating that it was dependent on the prior localization of these proteins. Addition of furazlocillin, a specific inhibitor of FtsI, prevented localization of FtsI even though FtsZ and FtsA localization occurred. Interestingly, the localization of FtsN was also prevented by furazlocillin. FtsZ displayed limited localization in furazlocillin-treated cells, whereas it was efficiently localized in FtsI-depleted cells. FtsW, another essential cell division protein, was also localized to the septum.
Azlocillin↗
Effect of PANTA on growth of Mycobacterium kansasii in BACTEC 12B medium.
Mycobacterium kansasii isolates from two patients showed relatively slow growth in BACTEC 12B medium (12B) (Becton Dickinson Diagnostic Instrument Systems, Sparks, Md.) compared with the more rapid growth of these isolates on solid media. This finding prompted an evaluation of the effect of PANTA (Becton Dickinson) on the growth rate of these isolates. Suspensions of one isolate from each of these two patients (A and B), six additional isolates from six other patients (C through H), and one M. kansasii American Type Culture Collection isolate were inoculated into 12B with PANTA, 12B with reconstituting fluid only, and Middlebrook 7H11 agar plates (Remel, Lenexa, Kans.). For the isolates from patients A and B, the average times to detection for 12B with PANTA, 12B with reconstituting fluid, and Middlebrook 7H11 agar were 12.3, 7.4, and 9.0 days, respectively. For the remaining six patient isolates and the American Type Culture Collection strain, the average times to detection for these media were 9.2, 8.1, and 9.6 days. Susceptibility tests performed with the isolates from patients A and B with the individual component antibiotics of PANTA and testing of four of the other isolates with nalidixic acid alone suggested that nalidixic acid exerts some degree of inhibition on the growth of M. kansasii. The eight patient isolates were also inoculated onto Lowenstein Jensen medium (Remel) and onto a variety of selective mycobacterial media containing nalidixic acid and other antimicrobial agents. All isolates showed some degree of inhibition on at least one of these selective media.
Amphotericin B↗
In vitro efficacy of Bay k 4999, a new ureido-penicillin, in combination with aminoglycosides against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Proteus strains.
The in vitro effects of Bay k 4999 in combination with gentamicin, tobramycin, amikacin sisomicin and netilmicin in bacteriostatic (MIC) and bactericidal (MBC) concentrations were compared using the checkerboard dilution technique against 20 different strains of Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and indole-positive-negative Proteus species. On average 63% of Bay k 4999-aminoglycoside (AG) combinations inhibited Pseudomonas, Proteus and Klebsiella strains additively and/or synergistically in bacteriostatic as well as in bactericidal concentrations as compared to only 14% additive or synergistic activity on E. coli. 35% of the combinations tested proved to be synergistic in K. pneumoniae, 20% in Proteus, 13% in Pseudomonas, but only 5% in E. coli. No significant differences between various Bay k 4999-AG combination effects could be demonstrated.
Amikacin↗