bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys
Authors: Forgue S T , Shyu W C , Gleason C R , Pittman K A , Barbhaiya R H
Published: June 2012

The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound. Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method. Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen. For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level. After administration of 87 to 1,502 mg/kg by i.v. infusion, CL (12.5 ml/min per kg) was again similar for all dose groups. Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable. No consistent differences among dose group mean Vss values were found. The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose. For the cynomolgus monkey, kinetic parameters for 5-min i.v. infusions were linearly related to dose over the range of 10 to 600 mg/kg. Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg. The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.
Clinical efficacy and levels of ciprofloxacin in tissue in patients with soft tissue infection
Authors: Licitra C M , Brooks R G , Sieger B E
Published: June 2012

The clinical efficacy of ciprofloxacin was evaluated with 21 patients with soft tissue infection due mainly to gram-negative aerobic bacteria. Clinical cure was noted in 16 patients (76%), and clinical improvement was noted in the remaining 5 patients (24%). In addition, levels of ciprofloxacin were measured in the sera and tissues of 11 patients. Mean concentrations in tissue averaged 1.75 times the levels in serum. Ciprofloxacin should provide serum and soft tissue concentrations above the MICs for most gram-negative aerobic bacteria.
Failure to demonstrate a consistent in vitro bactericidal effect of trimethoprim-sulfamethoxazole against enterococci
Authors: Najjar A , Murray B E
Published: June 2012

Controversy exists as to the in vitro and in vivo activities of trimethoprim-sulfamethoxazole (TMP-SMX) against enterococci. In this study, we investigated the in vitro activity of TMP-SMX in the type of Mueller-Hinton broth previously reported to give the lowest MICs and MBCs with enterococci. In all instances, MICs were less than or equal to 0.5 microgram/ml. The majority of tests showed MBCs of greater than 32 micrograms/ml, although there was some effect from varying the inoculum and the length of incubation after subculturing. Minor differences were noted when tests were repeated and between the results from microdilution and macrodilution tests and those obtained by the time-kill method. These results, as well as other reports, suggest that TMP-SMX should not be considered a reliable bactericidal agent against enterococci.
Susceptibility of anaerobic bacteria to FCE 22101
Authors: Nord C E , Lindmark A , Person I
Published: June 2012

The activity of FCE 22101 against 675 strains of anaerobic bacteria was determined by an agar dilution method. Its activity was compared with those of benzylpenicillin, piperacillin, cefoxitin, imipenem, clindamycin, metronidazole, chloramphenicol, vancomycin, fusidic acid, and bacitracin. FCE 22101 and imipenem (MIC, less than or equal to 0.5 mg/liter) were the most active agents against the anaerobic strains tested, except against Clostridium difficile strains. On the basis of these results, FCE 22101 appears to be a promising antimicrobial agent for treatment of anaerobic infections, and further clinical investigations are indicated.
In vitro and in vivo activity of NY-198, a new difluorinated quinolone
Authors: Hirose T , Okezaki E , Kato H , Ito Y , Inoue M , Mitsuhashi S
Published: June 2012

NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride] is a new difluorinated quinolone characterized by the presence of a C-methyl group at the 3 position of the piperazine moiety. It has a broad antibacterial spectrum. The in vitro antibacterial activity of NY-198 was almost the same as those of ofloxacin and norfloxacin, but far exceeded that of pipemidic acid. NY-198 was more active than norfloxacin against Pseudomonas maltophilia, Acinetobacter calcoaceticus, and anaerobic microorganisms. Cross resistance was not observed between NY-198 and various antibiotics including methicillin, gentamicin, and ampicillin. NY-198 had bactericidal activity at the MIC or slightly higher than the MIC. It showed excellent antibacterial activity against various systemic infections in mice. After oral administration, NY-198 was two times more active than or as active as ofloxacin and two to four times more active than norfloxacin.
Prevalence of macrolides-lincosamides-streptogramin B resistance and erm gene classes among clinical strains of staphylococci and streptococci
Authors: Jenssen W D , Thakker-Varia S , Dubin D T , Weinstein M P
Published: June 2012

A total of 332 staphylococcal and 263 streptococcal isolates from three hospital microbiology laboratories were tested with erythromycin, clindamycin, and vernamycin B alpha to determine the prevalence of macrolides-lincosamides-streptogramin B resistance. Constitutive resistance was detected in 28 Staphylococcus aureus isolates (15.5%), 53 coagulase-negative staphylococci (35.1%), and 20 streptococci (7.6%). Inducible resistance was observed in 13 S. aureus isolates (7.2%), 25 coagulase-negative staphylococci (16.6%), and 2 streptococci (0.8%). Eleven coagulase-negative staphylococci (7.3%) exhibited a novel phenotype, namely inducible resistance to erythromycin and vernamycin B alpha but not clindamycin. Among the staphylococci, two variants of the inducible phenotype detected with the agar diffusion assay correlated with the presence of classical ermA or ermC genes, respectively, by dot-blot analysis. The prevalence of the staphylococcal phenotypes were different in the hospitals surveyed, and there was an apparent inverse correlation between the resistance observed and the use of erythromycin in each hospital.
Spread of SHV-1 beta-lactamase in Escherichia coli isolated from fecal samples in Africa
Authors: Shaokat S , Ouellette M , Sirot D , Joly B , Cluzel R
Published: June 2012

Ninety-seven (42%) Escherichia coli strains isolated in Senegal from fecal samples produced beta-lactamases. Among them, 29 (30%) isolates produced SHV-1 beta-lactamase that was plasmid mediated. The plasmids belonged to four incompatibility groups. Various degrees of TEM-1 expression in the presence of SHV-1 were observed.
Fleroxacin (Ro 23-6240) distribution in canine prostatic tissue and fluids
Authors: Gasser T C , Graversen P H , Madsen P O
Published: June 2012

The distribution of fleroxacin (Ro 23-6240) in canine prostatic tissue and fluids was investigated under steady-state conditions during intravenous infusion. Mean ratios of fleroxacin concentration in tissue and fluids over concentration in plasma were 1.57 +/- 0.25 for prostatic tissue, 1.12 +/- 0.28 for prostatic secretion, and 0.93 +/- 0.14 for prostatic interstitial fluid. These levels and concentrations in urine were several times higher than the MIC for most pathogens that cause chronic bacterial prostatitis and urinary tract infection. The MICs for several isolates of Escherichia coli were only slightly affected by canine prostatic secretion, human prostatic tissue extract, and human urine. Clinical trials with fleroxacin appear justified for chronic bacterial prostatitis and urinary tract infection.
Bactericidal activity of deptomycin (LY146032) compared with those of ciprofloxacin, vancomycin, and ampicillin against enterococci as determined by kill-kinetic studies
Authors: Stratton C W , Liu C , Ratner H B , Weeks L S
Published: June 2012

This study used kill-kinetic methods to provide data on the bactericidal activity of subinhibitory (1/2 X MIC), inhibitory (1 x MIC), and suprainhibitory (4X, 6X, and 8X MIC) concentrations of deptomycin (LY146032) against strains of enterococci compared with those of ciprofloxacin, vancomycin, and ampicillin. Deptomycin was the most active agent tested, as determined by broth microdilution methods, with all strains being inhibited at concentrations less than or equal to 2 micrograms/ml. The kill-kinetic demonstrated that deptomycin had greater activity at all concentrations tested than the other cell wall-active agents; regrowth was seen, however, at lower concentrations. At higher concentrations (6X and 8X MIC), all agents tested demonstrated the same or less bactericidal activity than at 4X MIC, presumably due to the Eagle effect. Nevertheless, these results suggest that further evaluation of deptomycin as a therapeutic agent for serious enterococcal infections is warranted.
Biological activity of BO-1236, a new antipseudomonal cephalosporin
Authors: Nakagawa S , Sanada M , Matsuda K , Hazumi N , Tanaka N
Published: June 2012

BO-1236, a new cephalosporin having an N-methyl-5,6-dihydroxyisoindolinium moiety on the 3-methylene of the cephem, showed potent activity against gram-negative organisms, including Pseudomonas aeruginosa. The in vitro activity of BO-1236 was superior or comparable to that of ceftazidime, cefotaxime, and cefoperazone in susceptibility tests with clinical isolates. BO-1236 was significantly more active than ceftazidime against P. aeruginosa strains susceptible or resistant to ceftazidime or gentamicin or both. MBCs were usually close to MICs, both of which were influenced by inoculum size to about the same degree as those of the other beta-lactams. BO-1236 was stable to all types of beta-lactamases except type I oxyiminocephalosporin-hydrolyzing enzyme, by which BO-1236 was slightly hydrolyzed. BO-1236 showed protective activity superior to that of ceftazidime and cefotaxime in experimental infections in mice caused by two strains of P. aeruginosa and showed activity comparable to that of ceftazidime and cefotaxime against other gram-negative bacterial infections.
Influence of beta-lactam antibiotics and ciprofloxacin on cell envelope of Escherichia coli
Authors: Suerbaum S , Leying H , Kroll H P , Gmeiner J , Opferkuch W
Published: June 2012

The effects of subinhibitory concentrations of different beta-lactam antibiotics and one quinolone on the quantitative composition of the outer membrane (OM) of two strains of Escherichia coli, on lipid translocation into the OM, and on the production of capsular K1 polysaccharide were studied. The phospholipid/amino acid ratio was reduced in almost all OM preparations from antibiotic-treated bacteria. In one strain, antibiotic treatment increased the lipopolysaccharide/amino acid ratio. The amount of peptidoglycan fragments bound to the OM was increased by all the antibiotics. In pulse-chase experiments with a radioactive lipid precursor, ciprofloxacin, imipenem, and aztreonam inhibited phospholipid translocation into the OM. Furthermore, imipenem, cephaloridine, and ciprofloxacin induced a pronounced reduction of the production of capsular K1 polysaccharide. Thus, antibiotics seem to induce marked changes of the quantitative composition of the cell envelope of E. coli. Possible connections of these data with findings on the influence of antibiotics on functional parameters of the host-parasite relationship such as OM immunogenicity and serum resistance are discussed.
Environmental exposure of primary care personnel to ribavirin aerosol when supervising treatment of infants with respiratory syncytial virus infections
Authors: Rodriguez W J , Bui R H , Connor J D , Kim H W , Brandt C D , Parrott R H , Burch B , Mace J
Published: June 2012

The potential exposure to ribavirin aerosol in the environment was assessed in nurses caring for infants and children with severe lower respiratory tract infections due to respiratory syncytial virus. Ribavirin aerosol was administered via a ventilator, oxygen tent, or oxygen hood. Participants worked directly with infants receiving ribavirin for 20.0 to 35.0 h over a 3-day period. No toxic or adverse effects of ribavirin aerosol were observed in any of the 19 nurses studied, and ribavirin was not detected in erythrocytes, plasma, or urine collected after the potential exposure period.
Bactericidal activity of ciprofloxacin compared with that of cefotaxime in normal volunteers
Authors: Standiford H C , Drusano G L , Forrest A , Tatem B , Plaisance K
Published: June 2012

We compared ciprofloxacin (200 mg) with cefotaxime (2 g) when each was administered intravenously over a 30-min period to six volunteers in a crossover manner 1 week apart. To integrate the pharmacologic and microbiologic activity, inhibitory and bactericidal activities in serum were obtained for both antibiotics 1 and 6 h after administration against 10 strains of Escherichia coli, 10 strains of Klebsiella pneumoniae, 15 strains of Pseudomonas aeruginosa, and 10 strains each of methicillin-susceptible and -resistant Staphylococcus aureus. Geometric mean bactericidal titers for E. coli 1 h after the infusion were 1:60 for ciprofloxacin and 1:252 for cefotaxime, and for K. pneumoniae they were 1:20 and 1:256, respectively. However, geometric mean titers were poor for both antibiotics against methicillin-susceptible S. aureus (less than 1:2 for ciprofloxacin versus 1:5 for cefotaxime) and methicillin-resistant S. aureus (less than 1:2 for both antibiotics), as well as against P. aeruginosa (1:3 for ciprofloxacin versus 1:2 for cefotaxime). These data suggest that ciprofloxacin may be useful for the treatment of serious infections caused by E. coli and K. pneumoniae. However, caution is suggested when this dose of ciprofloxacin is used in situations in which septicemia is caused by P. aeruginosa or S. aureus and originates outside the urinary tract.
Human pharmacokinetics and tolerance of oral ganciclovir
Authors: Jacobson M A , de Miranda P , Cederberg D M , Burnette T , Cobb E , Brodie H R , Mills J
Published: June 2012

Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.
Plasmids and resistance to antimicrobial agents in Aeromonas sobria and Aeromonas hydrophila clinical isolates
Authors: Chang B J , Bolton S M
Published: June 2012

The antimicrobial susceptibilities of 75 Aeromonas isolates were determined by agar dilution. Differences in resistance patterns were observed between strains isolated from different geographic locations and between A. sobria and A. hydrophila isolates. Multiple resistance was common; however, only one conjugative plasmid was detected. This 110-megadalton plasmid mediated resistance to eight antibiotics.
In vitro susceptibility of 96 Capnocytophaga strains, including a beta-lactamase producer, to new beta-lactam antibiotics and six quinolones
Authors: Arlet G , Sanson-Le Pors M J , Casin I M , Ortenberg M , Perol Y
Published: June 2012

The in vitro activities of new beta-lactam antibiotics and new quinolones were studied against 96 Capnocytophaga strains, including a beta-lactamase-producing strain which was resistant to ampicillin, amoxicillin, carbenicillin, cephalothin, and cefamandole. All strains were susceptible to the combination of amoxicillin and clavulanic acid, ureidopenicillins, cefoxitin, broad-spectrum cephalosporins, and imipenem. Cephalothin and cefamandole did not show good activity against most strains. All Capnocytophaga spp. were uniformly susceptible to the five new quinolones tested.
Production of low-affinity penicillin-binding protein by low- and high-resistance groups of methicillin-resistant Staphylococcus aureus
Authors: Murakami K , Nomura K , Doi M , Yoshida T
Published: June 2012

Methicillin- and cephem-resistant Staphylococcus aureus (137 strains) for which the cefazolin MICs are at least 25 micrograms/ml could be classified into low-resistance (83% of strains) and high-resistance (the remaining 17%) groups by the MIC of flomoxef (6315-S), a 1-oxacephalosporin. The MICs were less than 6.3 micrograms/ml and more than 12.5 micrograms/ml in the low- and high-resistance groups, respectively. All strains produced penicillin-binding protein 2' (PBP 2'), which has been associated with methicillin resistance and which has very low affinity for beta-lactam antibiotics. Production of PBP 2' was regulated differently in low- and high-resistance strains. With penicillinase-producing strains of the low-resistance group, cefazolin, cefamandole, and cefmetazole induced PBP 2' production about 5-fold, while flomoxef induced production 2.4-fold or less. In contrast, penicillinase-negative variants of low-resistance strains produced PBP 2' constitutively in large amounts and induction did not occur. With high-resistance strains, flomoxef induced PBP 2' to an extent similar to that of cefazolin in both penicillinase-producing and -negative strains, except for one strain in which the induction did not occur. The amount of PBP 2' induced by beta-lactam antibiotics in penicillinase-producing strains of the low-resistance group correlated well with resistance to each antibiotic. Large amounts of PBP 2' in penicillinase-negative variants of the low-resistance group did not raise the MICs of beta-lactam compounds, although these strains were more resistant when challenged with flomoxef for 2 h. Different regulation of PBP 2' production was demonstrated in the high- and low-resistance groups, and factor(s) other than PBP 2' were suggested to be involved in the methicillin resistance of high-resistance strains.
Activity of lipid-soluble inhibitors of dihydrofolate reductase against Pneumocystis carinii in culture and in a rat model of infection
Authors: Queener S F , Bartlett M S , Jay M A , Durkin M M , Smith J W
Published: June 2012

Trimetrexate and BW301U (piritrexim isethionate), lipid-soluble inhibitors of dihydrofolate reductase, are potent inhibitors of the growth of Pneumocystis carinii in culture with WI-38 cells. Inhibition was observed with 0.1 microgram of trimetrexate or BW301U per ml. Trimethoprim is ineffective at 100 micrograms/ml in this culture system. Both trimetrexate and BW301U were effective as prophylactic agents against P. carinii pneumonia in rats; trimetrexate at 7.5 mg/kg protected 9 of 10 rats, and BW301U at 5 mg/kg protected 4 of 10.
Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods
Authors: Galgiani J N , Reiser J , Brass C , Espinel-Ingroff A , Gordon M A , Kerkering T M
Published: June 2012

Three groups of isolates, each comprising four isolates of Candida species, were selected for their diversity of susceptibilities to amphotericin B, flucytosine, or ketoconazole. The isolates were distributed in duplicate and in blinded fashion to three laboratories where a total of eight procedures were performed for each drug. From the decoded results, intralaboratory variability among replicate determinations was found usually to fall within a fourfold range. Interlaboratory variation, however, was 16-fold or greater for all isolates, ranging to 50,000-fold differences for some isolates. Relative susceptibilities of isolates within each method could be determined in 11 of the 24 drug-method combinations and agreed with the reference rank order in all but one instance. Our findings underscore the lack of agreement among laboratories for the susceptibility testing of yeasts but indicate that such differences could likely be resolved by standardization without loss of clinical value.
Synthesis and biological effects of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil
Authors: Chou T C , Kong X B , Fanucchi M P , Cheng Y C , Takahashi K , Watanabe K A , Fox J J
Published: June 2012

2'-Fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (FEAU) was synthesized, and its biological activities were compared with those of 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU). Earlier studies indicated that both compounds showed potent anti-herpes simplex virus activity, with a 50% effective dose (ED50) of less than 0.25 microM. In the present study the cell growth inhibitory activity of FEAU (ED50, 200 to 2,060 microM) was found to be about 100-fold less than that of FMAU. With an ED50 ranging from 630 to 3,700 microM, FEAU only weakly inhibited thymidine incorporation into DNA, as compared with FMAU with an ED50 of 9 to 28 microM. Following exposure to [2-14C]FEAU (100 microM), 0.48 pmol/10(6) cells per h was incorporated into the DNA of herpes simplex virus type 1-infected Vero cells, whereas no detectable incorporation was found in uninfected Vero cells or L1210 cells. The Ki of FEAU for thymidine kinase purified from human leukemic cells was greater than 150 microM. For herpes simplex virus type 1- and 2-encoded thymidine kinases, the Kis were 0.6 and 0.74 microM, respectively. Both FEAU and FMAU were relatively nontoxic for mice, with a 50% lethal dose of greater than 800 mg/kg per day (four intraperitoneal doses). However, the lethal dose of FEAU for dogs was 100 mg/kg per day (10 intravenous doses), a dose which is 40- to 80-fold greater than the toxic dose of FMAU. These results suggest that FEAU is a worthy candidate for further development as an antiherpetic agent.
Interactions of ciprofloxacin with clindamycin, metronidazole, cefoxitin, cefotaxime, and mezlocillin against gram-positive and gram-negative anaerobic bacteria
Authors: Whiting J L , Cheng N , Chow A W
Published: June 2012

A total of 598 clinical isolates of anaerobic bacteria were tested against ciprofloxacin by the agar dilution technique with 10(5) CFU on Wilkins-Chalgren medium. Selected strains representative of the six major genera of anaerobes relatively resistant to the quinolones were tested for interactions with ciprofloxacin in combination with clindamycin, metronidazole, cefoxitin, cefotaxime, or mezlocillin by using a checkerboard agar dilution technique. Cefotaxime-ciprofloxacin and clindamycin-ciprofloxacin were the most effective combinations, with 16% of all isolates and 44% of the Bacteroides fragilis group isolates responding synergistically to the former combination and 9% of all isolates and 37% of Peptostreptococcus isolates responding synergistically to the latter. Occasional synergy was seen with all other antibiotic combinations except for metronidazole-ciprofloxacin. Likewise, synergism was seen with all groups of anaerobes except for Fusobacterium species. Antagonistic interactions were observed only with a Peptostreptococcus intermedius strain tested against clindamycin-ciprofloxacin. These data suggest that combinations of ciprofloxacin with these agents may be useful for certain resistant anaerobic infections.
Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides
Authors: Gatell J M , Ferran F , Araujo V , Bonet M , Soriano E , Traserra J , SanMiguel J G
Published: June 2012

Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P less than 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides.
Steady-state pharmacokinetics of imipenem in febrile neutropenic cancer patients
Authors: Drusano G L , Plaisance K I , Forrest A , Bustamante C , Devlin A , Standiford H C , Wade J C
Published: June 2012

We ascertained the pharmacokinetics of imipenem in febrile granulocytopenic cancer patients. The values observed were both different from and significantly more variable than those observed in normal volunteers. Free drug concentrations exceeded the MIC for 90% of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains for greater than 6 h. The MIC for 90% of Pseudomonas aeruginosa strains was exceeded for 4 h. Because imipenem induces a 2-h postantibiotic effect in P. aeruginosa, it is promising as single-agent empiric therapy in this setting.
Increased susceptibility to cephamycin-type antibiotics of methicillin-resistant Staphylococcus aureus defective in penicillin-binding protein 2
Authors: Murakami K , Nomura K , Doi M , Yoshida T
Published: June 2012

A methicillin-resistant strain of Staphylococcus aureus which produced low-affinity penicillin-binding protein 2' (PBP 2') spontaneously lost PBP 2 when the strain was cultivated at 43 degrees C overnight. At 37 degrees C, the mutant had increased susceptibility to cephamycin-type beta-lactams, which showed high affinity for PBP 4. This result suggests that inhibition of PBP 4, in addition to that of PBP 2, is necessary to kill methicillin-resistant strains.
In vitro synergistic activity between bismuth subcitrate and various antimicrobial agents against Campylobacter pyloridis (C. pylori)
Authors: Van Caekenberghe D L , Breyssens J
Published: June 2012

The in vitro interactions between bismuth subcitrate and a variety of antimicrobial agents against 12 Campylobacter pyloridis (C. pylori) isolates were studied by the agar dilution checkerboard technique. The combination of bismuth subcitrate with the older quinolone, oxolinic acid, produced synergistic activity against all strains. This observation, however, could not be extended to the (aryl) fluoroquinolones, norfloxacin, ofloxacin, and difloxacin, since synergy was rare or absent when bismuth subcitrate was combined with these antibiotics. Among the other antimicrobial agents tested, rifampin and the beta-lactams frequently showed showed MICs for C. pyloridis similar to those of bismuth subcitrate.
Sequence of PSE-2 beta-lactamase
Authors: Huovinen P , Huovinen S , Jacoby G A
Published: June 2012

The nucleotide sequence of PSE-2 beta-lactamase, an enzyme that readily hydrolyzes both carbenicillin and oxacillin, has been determined. The deduced sequence of 266 amino acids contained 93 residues identical to those of OXA-2 beta-lactamase and the Ser-Thr-Phe-Lys tetrad also found in the active site of TEM-1 beta-lactamase.
In vitro evaluation of DuP 105 and DuP 721, two new oxazolidinone antimicrobial agents
Authors: Barry A L
Published: June 2012

DuP 105 and DuP 721 are two members of the oxazolidinones, a new class of synthetic antimicrobial agents with activity against gram-positive bacteria. In vitro tests compared the two new drugs with five other antimicrobial agents against 216 gram-positive isolates representing 4 genera and 10 species. DuP 721 MICs for 50% of the strains tested (MIC50s) ranged from 2.0 to 8.0 micrograms/ml, DuP 105 MIC50S ranged from 4.0 to 16 micrograms/ml, and vancomycin MIC50S ranged from 0.25 to 1.0 microgram/ml. Methicillin-resistant and -susceptible staphylococci were susceptible to ciprofloxacin, vancomycin, and DuP 721.
LY146032, alone and in combination with gentamicin, for the treatment of enterococcal pyelonephritis in the rat model
Authors: Sapico F L , Ginunas V J , Canawati H N , Montgomerie J Z
Published: June 2012

The in vivo and in vitro activity of LY146032 against Streptococcus faecalis GK was examined. The following MICs and MBCs in micrograms per milliliter were obtained: ampicillin, 0.8 and 1.5; vancomycin, 0.8 and 50; gentamicin, 12 and 25; and LY146032, 0.8 and 6. A time-kill-curve study involving approximately 10(6) organisms per ml showed a drop in the number of organisms of almost 2 log10 in the tube containing LY146032 (2 micrograms/ml) plus gentamicin (4 micrograms/ml) compared with bacterial numbers for the control at 4 h of incubation. However, regrowth was observed at 24 and 48 h, and no in vitro synergism was observed with the combination. A sample (1 ml) of overnight growth of this enterococcal strain at a concentration of 10(7) was then injected intravenously into 184 male Wistar rats weighing about 100 g each. After 12 days, 10 rats were sacrificed and the remaining ones were randomized into four treatment groups: (i) untreated control, (ii) LY146032 (3 mg) given subcutaneously, (iii) gentamicin (0.8 mg) given intramuscularly, and (iv) LY146032 plus gentamicin at the same dosages as when the drugs were used singly. The rats received antibiotics for 4 weeks twice daily, and approximately 10 rats in each group were sacrificed for quantitative kidney cultures at 1, 2, 4, and 6 weeks after the start of therapy. At the end of the 4- and 6-week periods, significantly better results were obtained with the combination of LY146032 plus gentamicin than with no treatment or treatment with single antibiotics.
Pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime in healthy volunteers
Authors: Boeckh M , Lode H , Borner K , Höffken G , Wagner J , Koeppe P
Published: June 2012

The pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime were investigated in 10 healthy volunteers. The pharmacokinetic parameters showed no significant differences (P less than 0.05) between single and combined administration. No antagonistic effects were observed in serum bactericidal activity with the combination against 20 gram-positive and 20 gram-negative locally isolated bacteria. A titer of greater than or equal to 1:8 was generated by the combination against all test strains except enterococci. Seven of ten volunteers developed a typical "red man's syndrome" during the administration of 1.0 g of vancomycin.
Cloning and expression of methicillin resistance from Staphylococcus epidermidis in Staphylococcus carnosus
Authors: Tesch W , Strässle A , Berger-Bächi B , O'Hara D , Reynolds P , Kayser F H
Published: June 2012

A 6.2-kilobase chromosomal DNA fragment from a methicillin-resistant Staphylococcus epidermidis strain was cloned into Staphylococcus carnosus by using staphylococcal plasmid pCA44 as the vector. The recombinant plasmid obtained, pBBB21, conferred methicillin resistance on its host and was responsible for the synthesis of a low-affinity penicillin-binding protein (PBP), PBP 2'. PBP 2' determined by the S. epidermidis DNA and expressed as a membrane-bound PBP in S. carnosus reacted with monoclonal antibodies directed against PBP 2' of Staphylococcus aureus origin, and the cloned S. epidermidis DNA hybridized to the methicillin (mec)-specific DNA from S. aureus. These findings point to a common origin of the methicillin resistance determinant in staphylococci.
In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl-fluoroquinolones
Authors: Waites K B , Cassell G H , Canupp K C , Fernandes P B
Published: June 2012

In vitro activities of the new macrolides clarithromycin, previously designated A-56268 (TE-031), and A-63075 and of the aryl-fluoroquinolones difloxacin (A-56619) and temafloxacin (A-62254) against 14 strains of Mycoplasma pneumoniae, 20 strains of Mycoplasma hominis, and 28 strains of Ureaplasma urealyticum were compared with that of erythromycin. All three macrolides inhibited growth of M. pneumoniae at less than 0.125 micrograms/ml. No macrolide was active against M. hominis. For five strains of U. urealyticum, MICs were greater than 256 micrograms/ml for all 3 macrolides. Excluding these, no other strain of U. urealyticum had an initial MIC of clarithromycin of greater than 1 microgram/ml, while five had initial MICs of erythromycin which were greater than 4 micrograms/ml. A-63075 was the least active of the three macrolides against ureaplasmas. Temafloxacin and difloxacin had similar activities against all three species, initially inhibiting 90% of M. pneumoniae strains at 2 and 8 micrograms/ml, 90% of M. hominis strains at 2 and 4 micrograms/ml, and 90% of U. urealyticum strains at 4 and 8 micrograms/ml, respectively. Additional pharmacokinetic and clinical trials with the new macrolides and quinolones with mycoplasmal or ureaplasmal infections are indicated.
Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses
Authors: Morrison P J , Mant T G , Norman G T , Robinson J , Kunka R L
Published: June 2012

The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.
Relationships between renal function and disposition of oral ciprofloxacin
Authors: Forrest A , Weir M , Plaisance K I , Drusano G L , Leslie J , Standiford H C
Published: June 2012

The relationships between creatinine clearance (CLCR) and the pharmacokinetics of oral ciprofloxacin were characterized. On the basis of these data, a dosage adjustment strategy, which incorporates the severity of infection and the size and renal function of the patient, was developed. An adaptive (feedback) control algorithm is proposed. A total of 32 subjects (8 normal, 8 anuric, and 16 with CLCR between 0.53 and 4.3 liters/h per 1.73 m2) were given a single 750-mg tablet of ciprofloxacin by mouth. Serial serum and urine samples were collected, assayed by high-pressure liquid chromatography, and comodeled. The population relationship between total apparent ciprofloxacin clearance (CL/f) and CLCR, both measured in liters per hour per 1.73 m2, was CL/f = 2.83 x CLCR + 21.8 (r = 0.69; P less than 0.001). The mean terminal half-life was not significantly related to CLCR but was much more variable in subjects with CLCR less than 3 liters/h per 1.73 m2 (F = 4.8; P less than 0.005). We conclude that patients with CLCR less than 1.2 liters/h per 1.73 m2 should receive two-thirds of the normal daily dose and that the dose interval should not be lengthened.
Human granulocyte activity against moxalactam-induced filamentous forms of Pseudomonas aeruginosa
Authors: Hammer M C , Baltch A L , Smith R P , Conroy J V , Bishop M , Michelsen P , Hill L
Published: June 2012

The purpose of this investigation was to study the kinetics of human granulocyte (polymorphonuclear leukocyte) phagocytosis and bactericidal activity against beta-lactam antibiotic (moxalactam)-induced filamentous bacterial forms of Pseudomonas aeruginosa. Ultrastructural observations of rod and filamentous forms of P. aeruginosa and their interaction with polymorphonuclear leukocytes are presented. Growth of P. aeruginosa 1348A in the presence of 4 micrograms of moxalactam per ml (one-fourth the MIC) resulted in filamentous forms. Phagocytosis of 75Se-radiolabeled filaments was more efficient than that of rods during the first 20 min of the assay; subsequently, phagocytosis of both forms was equal. The polymorphonuclear leukocyte bactericidal activities against both forms, which were standardized to equal bacterial particle and viable-cell counts, were equivalent. Considering the greater size and mass of filaments compared with those of rods, we concluded that filaments are more susceptible to both phagocytosis and killing than are bacillary forms.
Ceftazidime concentration in gallbladder tissue and excretion in bile
Authors: Shiramatsu K , Hirata K , Yamada T , Kimura H , Someya T , Usuki T , Karasawa G , Hayasaka H
Published: June 2012

Ceftazidime was given to 16 patients with cholelithiasis, and its concentrations in bile and the gallbladder wall were studied. The results suggest that ceftazidime is effective against biliary tract infection.
In vitro and in vivo studies of the effects of halogenated histidine analogs on Plasmodium falciparum
Authors: Panton L J , Rossan R N , Escajadillo A , Matsumoto Y , Lee A T , Labroo V M , Kirk K L , Cohen L A , Aikawa M , Howard R J
Published: June 2012

The effects of four halogenated analogs of histidine on in vitro growth of Plasmodium falciparum malaria parasites were monitored by measurement of the incorporation of 3H-labeled amino acids into parasite proteins and by light and electron microscopy. The uptake of [3H]isoleucine was reduced to 50% of the control value by addition of 70 microM 2-fluoro-L-histidine (2-F-HIS) or 420 microM 2-iodo-L-histidine (2-I-HIS). [3H]histidine uptake into acid-insoluble material was affected equally by these two compounds, 50% inhibition resulting at 200 microM concentration. Morphological analysis of parasite development proved a sensitive assay, since development of mature trophozoites was inhibited 50% by 25 microM 2-F-HIS or 100 2-I-HIS. Electron microscopy studies suggested different mechanisms of action of 2-F-HIS and 2-I-HIS on P. falciparum. 2-F-HIS produced a decrease in knob number at the erythrocyte surface and accumulation of electron-dense material under the parasite membrane. 2-I-HIS had no obvious effect on knobs or electron-dense material but affected parasite morphology. Surprisingly, 2-chloro-L-histidine and 2-bromo-L-histidine did not inhibit P. falciparum in vitro, even though their halogen atom substituents are intermediate in size between F and I atoms. 2-F-HIS and 2-I-HIS were tested in vivo against P. falciparum in owl monkeys (Aotus sp.) but were ineffective at doses that were nontoxic.
In vitro activity of E-1040, a novel cephalosporin with potent activity against Pseudomonas aeruginosa
Authors: Neu H C , Chin N X , Novelli A
Published: June 2012

The in vitro activity of E-1040 [(6R,7R)-3-[(4-carbamoyl-1-quinuclidinio)methyl]-7-[2-(5-amino-1,2 ,4- thiadiazol-3-yl)-(Z)-2-methoxyiminoacetoamido]-8-oxo-5-thia- 1- azabicyclo(4,2,0)oct-2-ene-2-carboxylate], a novel cephalosporin, was compared with that of ceftazidime, cefpirome, cefepime, imipenem, and gentamicin. E-1040 inhibited 50% of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus and Neisseria species at less than or equal to 0.25 microgram/ml, and the MIC for 90% of strains tested ranged from 0.06 to 2 micrograms/ml. It was two- to fourfold more active than ceftazidime and similar in activity to cefepime and cefpirome. It inhibited Enterobacter, Citrobacter, Serratia, and Morganella species that were resistant to ceftazidime. E-1040 inhibited imipenem-, piperacillin-, aztreonam-, and tobramycin-resistant P. aeruginosa. It was less active against Xanthomonas maltophilia and P. cepacia but inhibited other Pseudomonas species. The activity of E-1040 against staphylococci and hemolytic streptococci was similar to that of ceftazidime, but E-1040 was less active than cefepime and cefpirome. It did not inhibit Bacteroides spp. There was no inoculum effect or medium effect, and MBCs were within a dilution of MICs. Plasmid beta-lactamases TEM-1, TEM-2, TEM-3 (CTX-1), SHV-1, Staphylococcus aureus, PSE, and CARB did not hydrolyze E-1040. Chromosomal beta-lactamases P99 and K-1 did not hydrolyze E-1040; E-1040 had poor affinity for these enzymes, with a Ki of greater than 100 microM.
Sensitization by heat treatment of Escherichia coli K-12 cells to hydrophobic antibacterial compounds
Authors: Tsuchido T , Takano M
Published: June 2012

The sensitivities of intact and heat-injured cells of Escherichia coli K-12 to several antibacterial compounds were measured by the prolongation of growth delay. Cells exposed to sublethal heat became more sensitive to various hydrophobic compounds, such as medium-chain fatty acids, alkyl esters of p-hydroxybenzoic acid, and some kinds of antibiotics or dyes, than unheated cells; but there was a smaller or no increase in sensitivity to short-chain fatty acids, chloramphenicol, and vancomycin. The destruction by heat of a permeability barrier of the outer membrane may have sensitized the cells to hydrophobic compounds. The sensitization was much lower for a strain defective in lipopolysaccharide, which is important as a barrier against hydrophobic compounds.
Reverse transcriptases from human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIVMAC) are susceptible to inhibition by foscarnet and 3'-azido-3'-deoxythymidine triphosphate
Authors: Vrang L , Oberg B , Löwer J , Kurth R
Published: June 2012

Reverse transcriptases from human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) were investigated with respect to susceptibilities to the reverse transcriptase inhibitors foscarnet and 3'-azido-3'-deoxythymidine triphosphate (AZTTP). The different reverse transcriptases had the same sensitivity to foscarnet (50% inhibition at 0.10 to 0.16 microM). The Ki values for AZTTP were 0.01 to 0.02 microM for HIV-1 reverse transcriptase and 0.02 to 0.03 microM for HIV-2 and SIVMAC reverse transcriptases.
The cryptic tetracycline resistance determinant on Tn4400 mediates tetracycline degradation as well as tetracycline efflux
Authors: Park B H , Levy S B
Published: June 2012

Escherichia coli containing the cryptic tetracycline resistance determinant (class F) from the Bacteroides fragilis transposon Tn4400 on plasmid pGAT400 expressed a detoxification of tetracycline as well as an active efflux of tetracycline. This finding concurs with the report of detoxification for a related tetracycline resistance determinant from B. fragilis on Tn4351 (B. S. Speer and A. Salyers, J. Bacteriol. 170:1423-1429, 1987), which specifies a 10-fold-higher resistance than Tn4400. Inactivation of tetracycline occurred at an initial rate of congruent to 0.7 micrograms of tetracycline per h per 10(8) cells, as determined by biologic assay and chromatographic analysis. The detoxification is a chemical degradation which can occur in the absence of energy-dependent efflux. The products of this degradation were not substrates for active transport into susceptible cells or out of pGAT400-containing E. coli. These results indicate that Tn4400 mediates two functionally different mechanisms for tetracycline resistance: an active efflux of tetracycline and a degradation of tetracycline.
Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug
Authors: Lake-Bakaar D M , Abele G , Lindborg B , Soike K F , Datema R
Published: June 2012

The acyclic guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, (+/-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus infections in vitro. This report is concerned with the pharmacokinetic evaluation of the drug in rats and monkeys and its antiviral activity in African green monkeys infected with simian varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+/-)2HM-HBG. Elimination half-lives in plasma following intravenous administration to monkeys (100 mumol/kg of body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 +/- 0.4 ml/min per kg (mean +/- standard error). After oral administration, levels in plasma were low, with a maximum concentration of the drug of only 3.1 +/- 0.8 microM, a time to reach maximum concentration of drug of 2.7 +/- 0.4 h, and an oral bioavailability of 10.6 +/- 1.4%. Because of the low oral bioavailability, SVV-infected monkeys were treated intramuscularly with (+/-)2HM-HBG. (+/-)2HM-HBG at a dosage of 10 mg/kg of body weight per day allowed moderate viremia, whereas a dosage of 30 mg/kg of body weight per day strongly suppressed viremia with minimal numbers of virus plaques from blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (+/-)2HM-HBG is an effective inhibitor of SVV replication in vivo, despite the fact that leves of (+/-)2HM-HBG in plasma were low at extended periods of time and below the concentration of drug giving 50% inhibition of plaque formation obtained in vitro.