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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.  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
3.  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.
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PMCID: PMC176479  PMID: 3539010
4.  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
5.  Characterization of beta-lactamases in situ on polyacrylamide gels. 
An inhibitor-based characterization system which allowed the identification of beta-lactamases after isoelectric focusing on polyacrylamide gels was developed. This system, using potassium clavulanate and oxacillin, distinguished type I chromosomally mediated enzymes from other beta-lactamases of gram-negative bacteria.
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PMCID: PMC180628  PMID: 3492960
13.  Association between colistin resistance and broad-spectrum recipient deficiency in Klebsiella pneumoniae. 
A colistin-resistant mutant of Klebsiella pneumoniae served well as a donor but not as a recipient in conjugation. A nearly 1,000-fold difference between colistin-susceptible and colistin-resistant forms of this strain was observed by using donors of plasmids of four incompatibility groups. Recipient efficiency was not restored by filter matings.
PMCID: PMC180633  PMID: 3545071
14.  Mycobacterium avium-M. intracellulare isolates from patients with or without acquired immunodeficiency syndrome. 
Susceptibility testing and serotyping were performed on 57 isolates of Mycobacterium avium-M. intracellulare from patients with acquired immunodeficiency syndrome (AIDS) and 75 isolates from patients without AIDS. Susceptibility patterns and serotypes of AIDS isolates were significantly different from those of non-AIDS isolates. These results may partially explain the poor therapeutic response of M. avium-M. intracellulare infections in AIDS patients.
PMCID: PMC180630  PMID: 3813519
15.  Epidemiology of intestinal colonization by members of the family Enterobacteriaceae resistant to cefotaxime in a hematology-oncology unit. 
Intestinal colonization by members of the family Enterobacteriaceae resistant to cefotaxime was surveyed for 3 years in a hematology-oncology unit. Of 416 patients, 66 (15.9%) were colonized, each with a different strain. The incidence of intestinal carriage was not correlated with cefotaxime consumption in the ward but was strongly associated with individual exposure to cefotaxime.
PMCID: PMC180626  PMID: 3813517
16.  Activity of ciprofloxacin against multiply resistant strains of Pseudomonas aeruginosa, Staphylococcus epidermidis, and group JK corynebacteria. 
The susceptibilities of multiply resistant clinical isolates of Pseudomonas aeurginosa to ciprofloxacin, norfloxacin, and several beta-lactam and aminoglycoside antibiotics were evaluated. Ciprofloxacin also was compared with methicillin and vancomycin against methicillin-resistant Staphylococcus epidermidis and group JK corynebacteria. Ciprofloxacin exhibited the lowest MICs and MBCs for 90% of the isolates among all of the antibiotics tested against P. aeruginosa. In addition, ciprofloxacin exhibited excellent bactericidal activity against the gram-positive organisms. Clinical trials are necessary to confirm the in vitro results and monitor for emergence of resistance.
PMCID: PMC180624  PMID: 3101589
17.  Antistaphylococcal activity of a cyclic peptide, LY146032, and vancomycin. 
The inhibitory and bactericidal activities of a novel cyclic peptide antibiotic, LY146032, and vancomycin against oxacillin-susceptible and oxacillin-resistant staphylococci were compared. The MICs for 90% of strains were two- to fourfold higher for vancomycin than for LY146032. MBC/MIC ratios for all strains were less than or equal to 2. In killing rate studies with four strains of staphylococci, there was no detectable growth in the presence of 4X the MIC of either LY146032 or vancomycin after 24 h of incubation.
PMCID: PMC180623  PMID: 3028254
18.  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
19.  Penetration of cefixime into fibrin clots and in vivo efficacy against Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. 
The experimental model of infected fibrin clots in rabbits was used to study the penetration and in vivo activity of cefixime against Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. The respective MICs of cefixime against these strains were 0.25, 2, and 8 micrograms/ml. The clots were infected with 10(6) to 10(8) CFU/g. Groups of four animals for each strain received an intravenous injection of 100 mg of cefixime per kg over 30 min. High peak levels were observed in serum (146.5 micrograms/ml) and clots (15.8 micrograms/g), and the antibiotic was still detectable in the clots (0.6 micrograms/g) 24 h after administration. The respective serum and clot elimination half-lives were 0.7 and 5.0 h. The mean serum protein binding was 23.8 +/- 3.8%. Cefixime was highly bactericidal against K. pneumoniae and E. coli and reduced, over a 24-h period, their respective colony counts by 7.8 log10 and 6.2 log10 CFU/g of fibrin. It was less effective against S. aureus but still reduced the bacterial counts by 2.8 log10 CFU/g of fibrin. The present results demonstrate that cefixime, a new broad-spectrum oral cephalosporin, has a long tissue half-life which ensured, at the dose given here, good in vivo bactericidal activity against both gram-positive and gram-negative bacteria up to 24 h after administration of the antibiotic.
PMCID: PMC180618  PMID: 3545070
20.  Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function. 
The disposition of coadministered ticarcillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLCR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with reduced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimum concentrations in plasma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.
PMCID: PMC180615  PMID: 3492959
21.  In vitro studies simultaneously examining effect of oxacillin on uptake of radiolabeled streptomycin and on associated bacterial lethality in Staphylococcus aureus. 
We studied the effects of various concentrations of oxacillin on streptomycin uptake and killing for several strains of Staphylococcus aureus. When streptomycin was present in concentrations below the MIC, addition of oxacillin at concentrations greater than or equal to the MIC was associated with both significantly increased aminoglycoside uptake and killing. In contrast, when streptomycin was present in concentrations above the MIC, no increase of streptomycin uptake was noted with the addition of oxacillin, and killing was no greater than what would have been expected with a simply additive effect. Similar studies in a strain of S. aureus selected for high-level streptomycin resistance also demonstrated increased streptomycin uptake in the presence of concentrations of oxacillin above the MIC; however, killing was no greater than that seen with oxacillin alone. These studies provide data which are potentially important in designing a rational approach to clinical use of combination antibiotic therapy.
PMCID: PMC180611  PMID: 3643772
22.  Pharmacokinetics of cefoperazone in the parturient. 
Limited pharmacokinetic data for cefoperazone are available from the parturient. Because cefoperazone has a dual excretory pattern, primarily via the biliary system and secondarily via the kidney, pregnancy-induced physiologic alterations can influence its deposition and clearance. Twelve term parturients receiving cefoperazone prophylaxis after cesarean section were selected for study. After 2 g of cefoperazone was administered for 1 h intravenously, serial blood samples were assayed by high-pressure liquid chromatography. Plasma protein binding of cefoperazone was studied in vitro. The mean peak cefoperazone concentration +/- standard deviation was 169.9 +/- 60.4 micrograms/ml. The mean half-life was 152 min. Total serum clearance was 80.8 +/- 30.8 ml/min. The steady-state volume of distribution was 14.2 +/- 6.0 liters. All subjects had detectable trough levels at the end of the dosage interval, with a mean value of 6.5 +/- 5.2 micrograms/ml. Protein binding of cefoperazone for parturients was 74.3 +/- 10.9%, compared with 87.7 +/- 3.2% in nonpregnant controls (P less than 0.05). These data suggest that cefoperazone deposition can be greatly influenced by pregnancy. However, unlike several other new antimicrobial agents whose excretions are mainly renal, the cefoperazone half-life and thus trough concentration for the parturient more closely resemble that for the nonpregnant subject.
PMCID: PMC180610  PMID: 3813513
23.  In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. 
The in vitro and in vivo antibacterial activity of A-56268 (TE-031), the 6-O-methyl derivative of erythromycin, was compared with those of erythromycin and other reference drugs. A-56268 had the same spectrum of antibacterial activity as erythromycin. A-56268 was generally 1 log2 dilution more potent or equal to erythromycin against all organisms except haemophilus influenzae and Propionibacterium acnes, for which A-56268 was 1 log2 dilution and 3 log2 dilutions, respectively, less potent. The MBC of A-56268 and erythromycin was not significantly different from the MIC against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus epidermidis, and H. influenzae but was more than 2 log2 dilutions higher than the MICs for some Staphylococcus aureus strains. Human serum at a concentration of 50% did not change the in vitro potency of A-56268 or erythromycin. A-56268 was similar to erythromycin in being more active at pH 8.0 than at the physiologic pH of 7.3. The activity of A-56268 was synergistic with sulfamethoxazole against 4 of 12 strains of H. influenzae. In mouse protection tests, when administered orally A-56268 was more potent than erythromycin against H. influenzae, S. pyogenes, S. pneumoniae, and S. aureus. After subcutaneous administration the potencies of A-56268 and erythromycin were not statistically different from each other. A-56268 was more potent than erythromycin against Legionella infection in guinea pigs. The concentration of A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In mice, the peak levels in serum of A-56268 and erythromycin were similar after subcutaneous administration and seven times higher for A-56268 after oral administration. The serum half-life of A-56268 was approximately twice that of erythromycin after administration by both routes.
PMCID: PMC180609  PMID: 2949695
24.  Antileishmanial activity of liposome-encapsulated amphotericin B in hamsters and monkeys. 
Visceral leishmaniasis (kala-azar) results from parasitization of the macrophages of the liver, spleen, and the rest of the visceral reticuloendothelial system with Leishmania donovani. Pentavalent antimony is the drug of choice for leishmaniasis chemotherapy; amphotericin B (AmB) is active but is rarely used, because of drug toxicity. AmB encapsulated within macrophage-directed carriers (liposomes) has been used to treat humans with systemic mycoses complicating neoplastic diseases; dosages of up to 5 mg of encapsulated AmB per kg per day for greater than 14 days are without apparent kidney or liver toxicity. In the present work, greater than 99% of L. donovani parasites were eliminated from the liver and spleen of infected hamsters by one administration of 1.5 to 11 mg of liposome-encapsulated AmB (L-Amb) per kg. A total of 98 to 99% of hepatosplenic parasites were eliminated from squirrel monkeys by three administrations of 4 mg of L-AmB per kg. L-AmB was 170 to 750 times as active as antimony in hamsters, and approximately 60 times as active as antimony in monkeys. The demonstration that apparently nontoxic human dosages of L-AmB eliminate essentially all hepatosplenic parasites in hamster and primate models suggests that this preparation should be considered for clinical trial against kala-azar.
PMCID: PMC180605  PMID: 3813512
25.  In vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria and beta-lactamase stability of RS-533, a novel carbapenem. 
RS-533 is a novel carbapenem antibiotic. Its activity was compared with that of imipenem and the new cephalosporins, aztreonam, piperacillin, and tobramycin. RS-533 had activity comparable to that of imipenem, inhibiting the majority of the Enterobacteriaceae, streptococci, staphylococci, and Bacteroides species at concentrations of less than or equal to 2 micrograms/ml. RS-533 inhibited Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to ceftazidime, aztreonam, and cefoperazone, but RS-533 did not inhibit all methicillin-resistant Staphylococcus aureus or Pseudomonas maltophilia. It inhibited tobramycin-resistant members of the Enterobacteriaceae and Pseudomonas aeruginosa. RS-533 was stable against attack by common chromosomal and plasmid-mediated beta-lactamases and was an effective inhibitor of many beta-lactamases.
PMCID: PMC180602  PMID: 3545068

Results 1-25 (471)