Search tips
Search criteria

Results 1-25 (471)

Clipboard (0)
Year of Publication
Document Types
1.  Single-dose cephalexin therapy for acute bacterial urinary tract infections and acute urethral syndrome with bladder bacteriuria. 
The efficacy of single-dose therapy with 3 g of cephalexin was evaluated in 129 women with symptoms of acute uncomplicated lower urinary tract infections. Of 91 patients with significant bacteriuria, 61 (67%) were cured of their original infection; this was similar to the 54 to 79% cure rates reported in unselected populations of women of a wide age range treated for acute uncomplicated urinary tract infections with a single dose of amoxicillin or trimethoprim-sulfamethoxazole (J. Rosenstock, L. P. Smith, M. Gurney, K. Lee, W. G. Weinberg, J. N. Longfield, W. B. Tauber, and W. W. Karney, Antimicrob. Agents Chemother. 27:652-654, 1985; N. E. Tolkoff-Rubin, M. E. Wilson, P. Zuromskis, I. Jacoby, A. R. Martin, and R. H. Rubin, Antimicrob. Agents Chemother. 25:626-629, 1984). The cure rates of (87%) for our younger patients, those less than 25 years of age, was better than that (46%) for our patients over 40 years of age (P less than 0.001). Patients with infections that were negative in an antibody-coated bacteria test were cured at a significantly higher rate than those with infections that were positive in an antibody-coated bacteria test (71 versus 19%; P = 0.003). Those patients with infections caused by cephalexin-susceptible organisms were cured at a rate similar to that for patients with infections caused by cephalexin-resistant organisms (68 versus 50%; P = 0.62). The cure rate for suburban patients was 90%, versus 45% for inner-city patients (P = 0.008). Of the 28 women with acute urethral syndrome due to low-level bacteriuria, 27 were cured.
PMCID: PMC180398  PMID: 3717940
2.  Penicillin-binding proteins of penicillin-susceptible and -resistant pneumococci: immunological relatedness of altered proteins and changes in peptides carrying the beta-lactam binding site. 
There are several major differences between the penicillin-binding proteins (PBPs) of highly penicillin-resistant and -susceptible strains of pneumococci. The highest-molecular-size PBP 1a (98 kilodaltons [kDa]) of susceptible pneumococci is not detectable in resistant bacteria. Instead, resistant strains contain a PBP of smaller size: 92 and 94 kDa in South African strains 8249 and A95210, respectively, and 96 kDa in New Guinea strain 2955 (S. Zighelboim and A. Tomasz, Antimicrob. Agents Chemother. 17:434-442, 1980). Using antibodies prepared against PBP 1a of penicillin-susceptible pneumococci, we demonstrated that these anomalous-sized proteins in the resistant strains are immunologically related to PBP 1a of penicillin-susceptible bacteria. A second difference between the PBP patterns of strain 8249 and the susceptible pneumococci is that the 78-kDa PBP 2b is not detectable by the radioactive penicillin binding assay in the resistant strain. Using antibodies prepared against PBP 2b of susceptible cells, we demonstrated the presence of PBP 2b in membrane preparations from strain 8249 cells. Thus, the poor detection of this PBP appears to be related to its greatly decreased affinity for the antibiotic molecule. We also compared the patterns of penicillin-labeled peptides derived from PBPs of resistant and susceptible cells during partial proteolysis by V8 protease. Several changes were observable in small peptides carrying the beta-lactam binding site generated from the high Mr (PBP 1a-related) binding proteins. In contrast, no differences in the pattern of penicillin-labeled peptides were seen when the pattern of PBP 2a of susceptible pneumococci was compared with the peptide pattern of PBP 2a from resistant strains. One of the resistant isolates (strain 2955) also had a PBP 3 with a higher-than-normal molecular weight. This protein gave strong positive reaction with antibodies against PBP 3 of susceptible cells. Examination of the pattern of penicilloyl peptides generated from the susceptible and resistant PBP 3s during partial proteolysis revealed only differences which seem to reside distant from the beta-lactam binding site.
PMCID: PMC176479  PMID: 3539010
3.  Streptomycin accumulation by Bacillus subtilis requires both a membrane potential and cytochrome aa3. 
Cytochrome aa3 concentrations in the cytoplasmic membrane of Bacillus subtilis were altered by growth conditions, and the effects on the membrane potential (delta psi) in whole cells were measured. When cytochrome aa3 was absent, the magnitude of delta psi was not diminished by comparison with the delta psi measured in cells containing normal cytochrome aa3 concentrations. In addition, the energy-dependent uptake of proline and glutamate was comparable at both cytochrome aa3 concentrations. However, in the cytochrome aa3-deficient cell preparation, accumulation of the aminoglycoside antibiotic streptomycin was much lower than that of the cytochrome aa3-sufficient cells. When cells were cultured under conditions that stimulated higher than normal concentrations of cytochrome aa3, delta psi was also increased, and enhanced streptomycin accumulation was observed. Phenazine methosulfate-ascorbate was used both in delta psi measurements and in uptake studies to provide high rates of electron transport and maximal delta psi values. These results, taken together with those previously published (A. S. McEnroe and H. W. Taber, Antimicrob. Agents Chemother. 26:507-512, 1984) suggest that the uptake of streptomycin by B. subtilis requires adequate levels both of delta psi and cytochrome aa3.
PMCID: PMC180379  PMID: 2425730
4.  Alterations in kinetic properties of penicillin-binding proteins of penicillin-resistant Streptococcus pneumoniae. 
Earlier studies have shown that the highly penicillin-resistant South African Strains of pneumococci contain altered penicillin-binding proteins (PBPs) (S. Zighelboim and A. Tomasz, Antimicrob. Agents Chemother. 17:434-442, 1980). We now describe a detailed quantitative characterization of the reaction of radioactively labeled penicillin with the PBPs of the penicillin-susceptible and penicillin-resistant pneumococci and several intermediate-resistance-level genetic transformants as well. The altered binding of the antibiotic by the PBPs of resistant cells appears to be due to a combination of two factors: lower drug affinity and change in the cellular amounts of PBPs. No alteration in the rates of deacylation of the penicilloyl-PBPs of the resistant cells was detected.
PMCID: PMC176435  PMID: 3638932
5.  Enzymology and pathogenicity in mice of a herpes simplex virus type 1 mutant resistant to 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodocytosine. 
The deoxypyrimidine nucleoside analog 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodocytosine (FIAC) is a potent and selective inhibitor of herpes simplex virus type 1 in vitro (C. Lopez, K. A. Watanabe, and J. J. Fox, Antimicrob. Agents Chemother. 17:803-806, 1980). Isopycnographic analysis demonstrated that 1 microM FIAC inhibited herpes simplex virus DNA replication by more than 95% but inhibited cellular DNA replication by only 32%. Mutant herpes simplex virus type 1 selected resistant to FIAC displayed linked resistance to other nucleoside analogs, including arabinosylthymine and acyclovir. Lysates derived from Vero cells infected with FIAC-resistant virus showed markedly lower levels of thymidine kinase activity and were unable to phosphorylate selectively arabinosylthymine or FIAC, in contrast to lysates from cells infected with wild-type herpes simplex virus type 1. Finally, drug-resistant virus displayed a 6,000-fold decrease in pathogenicity when inoculated intraperitoneally into genetically susceptible A/J mice. These results indicate that resistance to deoxypyrimidine nucleoside analogs is due, at least in part, to alterations in viral thymidine kinase and is accompanied by decreased pathogenicity in vivo.
PMCID: PMC284171  PMID: 3015008
8.  Beta-lactamase-mediated imipenem resistance in Bacteroides fragilis. 
Imipenem has excellent antimicrobial activity owing in part to beta-lactamase stability. We found that only 2 of over 350 Bacteroides fragilis group clinical isolates were resistant to imipenem, with an MIC of more than 16 micrograms/ml. These two isolates from the Tufts Anaerobe Laboratory (TAL) were resistant to all other beta-lactam agents tested. The organisms were able to inactivate imipenem in broth cultures and contained similar beta-lactamases that were able to hydrolyze carbapenems, cephamycins, cephalosporins, and penicillins. The molecular sizes of the beta-lactamases in TAL2480 and TAL3636 were estimated to be 44,000 daltons. The novel beta-lactamase contained Zn2+ as a cofactor. An additional factor contributing to resistance was determined. The outer membranes of these two organisms were found to limit free diffusion of the drugs into the periplasm. This novel beta-lactamase, associated with a barrier to drug permeation, resulted in high-grade beta-lactam drug resistance.
PMCID: PMC176506  PMID: 3492173
9.  Bactericidal activity of ciprofloxacin against amikacin- and cefotaxime-resistant gram-negative bacilli and methicillin-resistant staphylococci. 
The MICs and MBCs of ciprofloxacin were determined for clinical isolates of antibiotic-resistant aerobic bacteria. Decreased susceptibility to ciprofloxacin of cefotaxime- and amikacin-resistant Serratia marcescens and amikacin-resistant Pseudomonas aeruginosa strains were noted. The data suggest that ciprofloxacin susceptibility should be carefully monitored in treating patients with hospital-acquired bacterial infections.
PMCID: PMC180508  PMID: 2942105
10.  Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli. 
The mechanism of penetration of quinolones through the bacterial outer membrane was studied with lipopolysaccharide-deficient and porin-deficient mutants. The data indicated that the lipopolysaccharide layer might form a permeability barrier for hydrophobic quinolones such as nalidixic acid but not for hydrophilic quinolones such as norfloxacin and ciprofloxacin. The results also showed that quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a high relative hydrophobicity appeared to permeate through both OmpF porin and phospholipid bilayers.
PMCID: PMC180431  PMID: 3521490
11.  Comparison of in vitro activity of quinolone antibiotics and vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus by time-kill kinetic studies. 
Quinolone antibiotics have been proposed as possible alternatives to vancomycin for methicillin-resistant Staphylococcus aureus infections. We investigated the activities of amifloxacin, ciprofloxacin, norfloxacin, and vancomycin by time-kill kinetic studies. Antibiotic concentrations of 0, 1.0, and 4.0 times the MIC were used against four strains of gentamicin- and methicillin-resistant S. aureus. Staphylococci were plated onto ciprofloxacin-containing agar at all time points, in repeat time-kill kinetic studies. Macrobroth dilution MICs and MBCs were determined. Ciprofloxacin levels were measured by bioassay. Replica plating was performed from the original susceptible inoculum (MIC, 0.125 micrograms/ml) onto ciprofloxacin-supplemented agar. At 4.0 times the MIC, only with ciprofloxacin was there regrowth at 24 and 48 h. All four strains of staphylococci grew on agar supplemented with 1 microgram of ciprofloxacin per ml; three of four grew on agar supplemented with 2 micrograms of ciprofloxacin per ml. MICs and MBCs for these resistant clones ranged from 8 to 32 micrograms/ml. No degradation in activity or amount of ciprofloxacin could be detected in the bioassay. Replica-plated staphylococci grew on agar containing 1 microgram/ml but not higher concentrations of ciprofloxacin at 48 h. Amifloxacin and norfloxacin sustained bactericidal activity comparable to that of vancomycin. We conclude that heteroresistant subpopulations of gentamicin- and methicillin-resistant S. aureus can emerge under antibiotic selection pressure. Such resistant clones may then mutate in the presence of subinhibitory concentrations of antibiotic to higher levels of ciprofloxacin resistance.
PMCID: PMC180601  PMID: 3643771
12.  Effect of clavulanic acid on the activity of ticarcillin against Pseudomonas aeruginosa. 
We studied the ability of clavulanic acid (CA) to induce beta-lactamase in Pseudomonas aeruginosa isolates and what effect this might have on the susceptibilities to beta-lactam agents. We first used a disk approximation method to test 4 laboratory and 16 clinical P. aeruginosa isolates against antipseudomonal beta-lactam agents for truncation by CA and found this to be very common. All antimicrobial compounds except imipenem demonstrated truncation in the vicinity of CA. We also evaluated the extent to which chromosomal beta-lactamase is induced by CA and found this to occur to some degree in most isolates and to be dependent on the concentration of CA. Finally, we performed time kill curves on these isolates to compare bacterial growth in ticarcillin alone with growth in ticarcillin-CA (the CA at 2 or 4 micrograms/ml). We found that CA at this concentration has neither an antagonistic nor a synergistic antibacterial effect in combination with ticarcillin.
PMCID: PMC176485  PMID: 3098162
14.  Survey of anaerobic susceptibility patterns in Canada. 
The in vitro activity of penicillin, cefoxitin, moxalactam, ticarcillin, clindamycin, chloramphenicol, and metronidazole against 590 anaerobic isolates collected from five Canadian hospitals during 1984 was determined by an agar dilution technique. Cefoxitin, clindamycin, chloramphenicol, and metronidazole were very active against most of the isolates. No major regional differences in the susceptibility patterns were observed.
PMCID: PMC176539  PMID: 3800358
15.  Activity of fluconazole (UK 49,858) and ketoconazole against Candida albicans in vitro and in vivo. 
Fluconazole (UK 49,858), a new orally administered bis-triazole, was compared with ketoconazole for activity in synthetic broth dilution susceptibility tests against Candida albicans and also in treatment of experimental systemic candidal infections in rats. In vitro studies indicated that fluconazole activity is less sensitive to acidic medium than is that of ketoconazole. At physiologic pH, fluconazole was approximately 16-fold less active than ketoconazole against 35 representative isolates of C. albicans. Two additional isolates (K-1 and K-3) recovered from patients who had failed ketoconazole therapy were 32- to 64-fold more resistant than the median of each drug for other isolates. In animal studies, fluconazole was very effective in prolonging survival of rats infected with a representative candidal strain. With an inoculum sufficient to kill 29 of 38 sham-treated animals, only 1 of 18 animals treated with 0.5 mg of fluconazole per kg per day died compared with 13 of 20 animals treated with 10.0 mg of ketoconazole per kg per day. However, when similar fluconazole treatment was administered to rats infected with the more resistant strain, K-1, no prolongation of survival was found. Thus, in vivo and in vitro results between strains correlated well for fluconazole. However, in comparing results between drugs, ketoconazole was 16-fold more active in vitro and fluconazole was 20-fold more active in vivo. This discrepancy may be due to drug distribution, modes of drug metabolism, or other pharmacologic differences between the two agents.
PMCID: PMC180572  PMID: 3022641
16.  Possible physiological functions of penicillin-binding proteins in Staphylococcus aureus. 
There are four penicillin-binding proteins (PBPs) in Staphylococcus aureus, of which PBPs 2 and 3 are essential. Cefotaxime binds selectively to PBP 2, and cephalexin binds to PBP 3, each at its respective MIC. The morphology of S. aureus strains grown in the presence of the two antibiotics was examined by phase-contrast and scanning electron microscopy. Exposure of the cells to cefotaxime at concentrations at which it bound selectively to PBP 2 resulted in the extrusion of cytoplasm and cell lysis, whereas exposure to cephalexin at concentrations at which it bound exclusively to PBP 3 resulted in cell enlargement and the cessation of septation. The latter morphological response was very similar to that produced by norfloxacin. The results suggest that in S. aureus, PBP 2 may be the primary peptidoglycan transpeptidase, and PBP 3 may be involved in septation.
PMCID: PMC176403  PMID: 3521479
17.  In vitro activity of imipenem against enterococci and staphylococci and evidence for high rates of synergism with teicoplanin, fosfomycin, and rifampin. 
The in vitro activities of imipenem alone and in combination with teicoplanin, fosfomycin, and rifampin were tested against clinical isolates of enterococci and staphylococci. In both groups of organisms, the three combinations demonstrated high rates of synergism in both checkerboard and time-kill studies.
PMCID: PMC176544  PMID: 2948444
19.  Serum bactericidal activity and killing rate for volunteers receiving imipenem, imipenem plus amikacin, and ceftazidime plus amikacin against Pseudomonas aeruginosa. 
Serum bactericidal activity against 20 strains of Pseudomonas aeruginosa was studied in 10 volunteers after administration of imipenem (25 mg/kg), imipenem (25 mg/kg) plus amikacin (7.5 mg/kg), and ceftazidime (25 mg/kg) plus amikacin (7.5 mg/kg). Eight strains were susceptible and 12 were resistant to ticarcillin. Serum levels were measured microbiologically after 30 and 60 min and were, respectively, 97 and 46 micrograms/ml for imipenem given alone and 79 and 45 micrograms/ml for imipenem given with amikacin. Despite the very large dose of imipenem used, imipenem and imipenem plus amikacin appeared slightly less active than ceftazidime plus amikacin (P less than or equal to 0.1; Wilcoxon matched-pairs test), with respective median titers at 30 min of 1:128, 1:128, and 1:256 against ticarcillin-susceptible strains and 1:32, 1:32, and 1:64 against ticarcillin-resistant strains; however, more than 90% of the serum determinations, regardless of the regimen, had a serum bactericidal activity greater than or equal to 1:8. Amikacin significantly increased the rate of killing in serum of P. aeruginosa by imipenem. Imipenem plus amikacin appeared as effective as ceftazidime plus amikacin in reducing the viable counts of P. aeruginosa after 24 h of incubation.
PMCID: PMC176448  PMID: 3092729
20.  Aztreonam concentration in abdominal tissues and bile. 
Abdominal tissue, serum, and bile samples were obtained from 37 patients given a single, 2-g intravenous infusion of aztreonam immediately prior to an elective abdominal operation. Samples were obtained at 0 to 6 h after dosing. Mean concentrations in tissues and fluids and specimen/serum rations are reported. Levels in tissue and bile exceeded the reported MICs for 90% of most members of the family Enterobacteriaceae for up to 6 h.
PMCID: PMC180509  PMID: 3729362
21.  Transfer of beta-lactamase-associated cefoxitin resistance in Bacteroides fragilis. 
A cefoxitin-resistant Bacteroides fragilis isolate, TAL 4170, which inactivates cefoxitin, was able to transfer beta-lactamase-mediated cefoxitin resistance to a susceptible B. fragilis recipient. Cefoxitin-resistant transconjugants acquired a new beta-lactamase with a pI of 8.1 and were able to inactivate cefoxitin and retransfer cefoxitin resistance. No plasmids were detected in the donor or transconjugants.
PMCID: PMC284179  PMID: 3488018
22.  Involvement of outer membrane of Pseudomonas cepacia in aminoglycoside and polymyxin resistance. 
Pseudomonas cepacia was found to be resistant to the outer membrane-permeabilizing effects of aminoglycoside antibiotics, polymyxin B, and EDTA. Permeabilization of P. cepacia to the fluorescent probe 1-N-phenylnaphthylamine was not achieved at concentrations 100- to 1,000-fold above those required to permeabilize Pseudomonas aeruginosa. Furthermore, in contrast to P. aeruginosa cells, intact cells of P. cepacia did not bind the fluorescent probe dansyl-polymyxin. However, purified lipopolysaccharide (LPS) from P. cepacia bound dansyl-polymyxin with approximately the same affinity as did LPS from P. aeruginosa. Also, binding of dansyl-polymyxin to P. cepacia (and P. aeruginosa) LPS was inhibited by polymyxin B, streptomycin, gentamicin, and Mg2+. These data suggest that P. cepacia does not utilize the self-promoted pathway for aminoglycoside uptake and that the outer membrane is arranged in a way that conceals or protects cation-binding sites on LPS which are capable of binding polycations such as aminoglycosides or polymxyin.
PMCID: PMC180620  PMID: 3028253
23.  Penetration of aztreonam into cerebrospinal fluid and brain of noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa. 
This study examined the penetration of aztreonam into the cerebrospinal fluid (CSF) and brain in noninfected rabbits and rabbits with experimental meningitis caused by Pseudomonas aeruginosa. Animals received either 600 or 1,200 mg of aztreonam administered intravenously over 6 h. Aztreonam did not readily enter the CSF in the absence of meningitis. In noninfected animals, mean concentrations in the CSF ranged from 1.1 to 3.0 micrograms/ml with the 600-mg dose and from 2.3 to 4.7 micrograms/ml with the 1,200-mg dose. In contrast, mean concentrations of aztreonam in the CSF were significantly higher (P less than 0.01) at each sampling time in rabbits with experimental meningitis caused by P. aeruginosa. They ranged from 10.2 to 14.6 micrograms/ml with the 600-mg dose and from 29 to 40 micrograms/ml with the 1,200-mg dose. Although concentrations in the brain measured at 6 h tended to be higher in infected rabbits, this difference was not statistically significant. Aztreonam therapy produced a substantial decline in CSF bacterium counts over 6 h: mean CSF counts decreased 2.4 log10 CFU/ml in the 600-mg dose group and 3.0 log10 CFU/ml in the 1,200-mg dose group. The results of this study suggest that aztreonam may be useful in the therapy of meningitis caused by P. aeruginosa.
PMCID: PMC176517  PMID: 3099641
24.  Difloxacin metabolism and pharmacokinetics in humans after single oral doses. 
By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.
PMCID: PMC176515  PMID: 3800345
25.  Penetration of amoxicillin and potassium clavulanate into the cerebrospinal fluid of patients with inflamed meninges. 
A single intravenous dose of 2.0 g of amoxicillin and 0.2 g of potassium clavulanate was given to patients with bacterial meningitis, and the pharmacokinetics of both drugs in the cerebrospinal fluid (CSF) and plasma were evaluated. Twenty-one patients aged 14 to 76 years were studied. Both amoxicillin and potassium clavulanate were detectable in the CSF as early as 1 h and reached peak concentrations by approximately 2 h. The highest mean CSF concentrations were 2.25 micrograms/ml for amoxicillin and 0.25 micrograms/ml for potassium clavulanate and were found in patients with moderately or severely inflamed meninges. The CSF penetration relative to plasma for amoxicillin and potassium clavulanate was 5.8 and 8.4%, respectively. These levels suggest that the amoxicillin-potassium clavulanate combination may be effective for the treatment of bacterial meningitis caused by beta-lactamase-producing pathogens.
PMCID: PMC180584  PMID: 3777911

Results 1-25 (471)