bluuebunny/crossref_metadata_2025 huggingface dataset:
Imipenem- and meropenem-resistant mutants of Enterobacter cloacae and Proteus rettgeri lack porins
Authors: Raimondi A , Traverso A , Nikaido H
Published: June 2012

Carbapenems such as imipenem and meropenem are not rapidly hydrolyzed by commonly occurring beta-lactamases. Nevertheless, it was possible, by mutagenesis and selection, to isolate mutant strains of Enterobacter cloacae and Proteus rettgeri that are highly resistant to meropenem and imipenem. Two alterations were noted in the E. cloacae mutants. First, the mutant strains appeared to be strongly derepressed in the production of beta-lactamases, which reached a very high level when the strains were grown in the presence of imipenem. Second, these mutants were deficient in the production of nonspecific porins, as judged by the pattern of outer membrane proteins as well as by reconstitution assays of permeability. As with most porin-deficient mutants, their cultures were unstable, and their cultivation in the absence of carbapenems rapidly led to an overgrowth of porin-producing revertants. Analysis of the data suggests that the synergism between the lowered outer membrane permeability and the slow but significant hydrolysis of carbapenems by the overproduced enzymes can explain the resistance phenotypes quantitatively, although the possibility of alteration of the target cannot be excluded at present. With P. rettgeri mutants, there was no indication of further derepression of beta-lactamase, but the enzyme hydrolyzed imipenem much more efficiently than the E. cloacae enzyme did. In addition, the major porin was absent in one mutant strain. These results suggest that a major factor for the carbapenem resistance of these enteric bacteria is the porin deficiency, and this conclusion forms a contrast to the situation in Pseudomonas aeruginosa, in which the most prevalent class of imipenem-resistant mutants appears to lack the specific channel protein D2 yet retains the major nonspecific porin F.
Comparison of spiral gradient and conventional agar dilution for susceptibility testing of anaerobic bacteria
Authors: Wexler H M , Molitoris E , Jashnian F , Finegold S M
Published: June 2012

Antimicrobial susceptibility tests were performed on brucella laked blood agar with 340 isolates and 14 antimicrobial agents by the standard agar dilution technique and the spiral gradient technique in which antibiotic concentrations were established by diffusion from the agar surface. For comparison, spiral gradient MICs were determined by calculating antimicrobial concentrations at growth endpoints and rounding up to the next twofold incremental concentration. The cumulative percentage of strains susceptible at the breakpoint determined from spiral gradient data was within 10%, generally, of the percentage of strains susceptible at the breakpoint determined from agar dilution data. The overall agreement between the two techniques (within one doubling dilution) was 90.6%. The spiral gradient agar dilution technique is a reasonable alternative to the conventional agar dilution technique for susceptibility testing of anaerobic bacteria.
Long-term prophylaxis with norfloxacin versus nitrofurantoin in women with recurrent urinary tract infection
Authors: Raz R , Boger S
Published: June 2012

A total of 102 women with recurrent urinary tract infections were included in this open randomized study; 55 received 200 mg of norfloxacin daily and 47 received 50 mg of nitrofurantoin daily over 6 months. Fifty-three and 41 women from the norfloxacin- and nitrofurantoin-treated groups, respectively, completed the 6-month follow-up period. Forty-four (81%) of the norfloxacin-treated patients and 27 (65%) of the nitrofurantoin-treated patients remained free of symptoms (P = 0.05), and urine samples from 49 (92.4%) and 29 (70.7%) of the patients, respectively, were sterile (P less than 0.005). Side effects occurred with similar frequencies in both groups (15 and 17%) but were more severe in the women who received nitrofurantoin. Despite the better results obtained with norfloxacin, the difference in the costs of the two agents must be considered.
In vitro and in vivo studies of ME1228, a new parenteral cephalosporin with potent activity against Pseudomonas aeruginosa
Authors: Miyazaki S , Miyazaki Y , Tsuji A , Nishida M , Goto S
Published: June 2012

The therapeutic effect of ME1228, a new parenteral cephalosporin, was compared with that of broad-spectrum cephems in normal and neutropenic mice infected with various species of bacteria. The results showed that ME1228 was more active than were the other cephems against infections with various pathogens.
Pharmacokinetics of 2',3'-dideoxyinosine in monkeys
Authors: Qian M X , Finco T S , Swagler A R , Gallo J M
Published: June 2012

Comparison of the pharmacokinetic parameters obtained for dideoxyinosine (ddI) in monkeys with those obtained for humans indicates that the monkey is an appropriate animal model for ddI pharmacokinetics in humans. Following intravenous administration of 20 mg of ddI per kg of body weight and measurement of ddI in plasma and urine by high-performance liquid chromatography, pharmacokinetic parameters were determined by noncompartmental analysis. Total systemic clearance was 0.74 liters/h/kg, volume of distribution was 0.92 liters/kg, and the elimination half-life of ddI was 1.22 h. The pharmacokinetics of ddI in five monkeys were determined following intravenous administration of 20 mg/kg and were found to be comparable to those obtained in patients with AIDS.
Use of high-performance liquid chromatography to monitor stability of tetracycline and chlortetracycline in susceptibility determinations
Authors: Ray A , Newton V
Published: June 2012

Trypticase soy broth and nutrient broth were used in the antimicrobial susceptibility testing of tetracycline and chlortetracycline with Bacillus subtilis. The stability of the antibiotics in both media at an incubation temperature of 37 degrees C was monitored by high-performance liquid chromatography. It was found that Trypticase soy broth has limited application in susceptibility testing for the tetracycline congeners tested and that chlortetracycline is more unstable than tetracycline.
Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes
Authors: Cavalieri S J , Sanders C C , New C
Published: June 2012

The ability of beta-lactamase inhibitors to induce class I beta-lactamases in certain organisms in vitro suggests a potential for antagonism in vivo. Therefore, a study was designed to assess the ability of sulbactam and clavulanate to induce beta-lactamases in two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and Pseudomonas aeruginosa both in vitro and in vivo. Induction in vitro was observed only with S. marcescens and P. aeruginosa and generally only when inhibitor concentrations greater than 2 micrograms/ml were examined. A mouse model of lethal infection, designed to detect in vivo antagonism arising from beta-lactamase induction, was used to determine what effect sulbactam and clavulanate would have on the 50% protective doses (PD50s) of cefoperazone and ticarcillin. Antagonism (a significant increase in the PD50) was observed in only 4 of 32 tests. Three of these involved antagonism of cefoperazone by clavulanate, and one involved antagonism of cefoperazone by sulbactam. In 6 of 32 tests, enhancement of efficacy (a significant decrease in PD50) was observed. In four of these, sulbactam enhanced cefoperazone; in one, sulbactam enhanced ticarcillin; and in one, clavulanate enhanced ticarcillin. Four of the six cases of enhancement occurred when the beta-lactamase inhibitor was given at the time of challenge. None of these positive or negative in vivo effects were predicted by in vitro tests. These data suggest that beta-lactamase inhibitors can influence the in vivo potency of their companion drug in both a beneficial and detrimental fashion against organisms with class I beta-lactamases and that these effects cannot be predicted from in vitro assays.
Suppression of Leishmania donovani by oral administration of a bis(benzyl)polyamine analog
Authors: Baumann R J , McCann P P , Bitonti A J
Published: June 2012

We reported previously that intraperitoneal administration of a bis(benzyl)polyamine analog, MDL 27,695, suppressed both pentavalent antimony (Sbv)-susceptible and -resistant Leishmania donovani in vivo. The present studies were performed to optimize parasite suppression by parenteral administration and to evaluate the efficacy of oral treatment with MDL 27,695. L. donovani infections in BALB/c mice were suppressed greater than 99% after intraperitoneal dosing for 20 days with a total dose of 150 mg of MDL 27,695 per kg of body weight or 560 mg of Sbv per kg. Suppression was not increased by a total dose of 400 mg of MDL 27,695 per kg given for 20 days. In mice treated for 2, 4, or 7 days with either MDL 27,695 or Sbv (total doses of 60, 120, and 210 mg/kg, respectively), more liver parasites were killed with MDL 27,695 than with Sbv. Assessment of livers posttreatment showed that parasite killing continued for at least 3 days in MDL 27,695-treated mice but not for longer than 1 day in Sbv-treated mice. Intramuscular administration of drugs resulted in 92% parasite suppression by MDL 27,695 (15 mg/kg three times per day for 5 days) and 64% suppression by Sbv (60 mg/kg once per day for 5 days). Dosing of mice by oral gavage with 100 mg of MDL 27,695 per kg twice per day for 14 days resulted in 99.7% parasite suppression, and the 50% effective dose was approximately 11 mg of MDL 27,695 per kg. MDL 27,695 represents an effective new drug potentially useful for oral or parenteral treatment of visceral leishmaniasis.
Altered tobramycin pharmacokinetics during chemoprophylaxis in bladder surgery
Authors: Bressolle F , Joubert P , Gouby A , Costa P , Laracine M , Rebière T
Published: June 2012

The effect of bladder surgery on the pharmacokinetics of tobramycin in hospitalized patients was studied. Fourteen patients with vesical neoplasia undergoing urinary tract surgery were given tobramycin in a dose of 2 mg/kg of body weight. Each patient received the dose at the induction of anesthesia, about 1 h before surgical incision. For seven patients, the drug was also administered 3 weeks later when nutritional conditions were normal. The pharmacokinetic parameters were determined by a two-compartment open model. Except for renal clearance, no significant difference appeared between pharmacokinetic parameters determined from serum data during peri- and postoperative periods. During this work, tobramycin excretion in urine was studied. Twenty-four hours after drug administration, the mean urine tobramycin levels were 25.5 +/- 9.06 and 41.6 +/- 21.5 micrograms/ml after peri- and postoperative administration, respectively; these values were higher than the MICs for most urinary tract pathogens. Seventy-two hours after perioperative administration, the mean value was still elevated (3.54 micrograms/ml), but 72 h after postoperative administration, the urinary tobramycin concentration was not detectable. The percentages of tobramycin recovered unchanged in urine were 54 and 79% after peri- and postoperative administration, respectively. When tobramycin was administered during surgery, a long terminal log-linear phase, with a mean half-life of 25.6 h, was detected. The ratio of renal clearance to total body clearance was 0.52 and 0.79 after peri- and postoperative administration, respectively.
Treatment of experimental cryptococcosis with SCH 39304 and fluconazole
Authors: Negroni R , Costa M R , Finquelievich J L , Iovannitti C , Agorio I , Tiraboschi I N , Loebenberg D
Published: June 2012

The efficacy of two triazoles, SCH 39304 and fluconazole, in the treatment of disseminated cryptococcosis in Wistar rats was determined. A total of 160 rats were inoculated intracardiacally with 2 x 10(5) cells of Cryptococcus neoformans. Both drugs were administered by gavage once daily, at three doses (8, 16, and 32 mg/kg/day). Two treatment schedules were followed: (i) treatment began 1 week after infection and continued for 3 weeks and (ii) prophylaxis treatment began 3 days before infection and continued an additional 3 weeks. Evaluation was based on (i) macroscopic examination of lungs, (ii) microscopic examination of brains and lungs, (iii) histopathology of brains and lungs, and (iv) determination of number of CFU in brains. The number of CFU was the best measure of activity. SCH 39304 was more active than fluconazole in both regimens, and, prophylactically, SCH 39304 was able to achieve biological cures.
Measurement of the concentration of amphotericin B in brain tissue of scrapie-infected hamsters with a simple and sensitive method
Authors: Casaccia P , Ladogana A , Xi Y G , Ingrosso L , Pocchiari M , Silvestrini M C , Cittadini A
Published: June 2012

A simple, sensitive, and reproducible assay for the measurement of the amphotericin B concentration in tissue extracts was developed by using the fourth derivative of the absorption spectrum of amphotericin B between wavelengths of 330 and 430 nm. The amphotericin B concentration in spleen and brain was proportional to the total amount administered. The amphotericin B concentration in the brain was highly correlated with the increase in the mean incubation period of intracerebrally scrapie-infected hamsters.
Inhibition by quinolones of DNA gyrase from Staphylococcus aureus
Authors: Tanaka M , Sato K , Kimura Y , Hayakawa I , Osada Y , Nishino T
Published: June 2012

In order to clarify the mechanism of action of quinolones against Staphylococcus aureus, the subunit A and B proteins of DNA gyrase were separately purified from a crude extract of S. aureus FDA 209-P. The reconstituted enzyme exhibited ATP-dependent DNA supercoiling activity. The inhibitory effects of quinolones on the supercoiling activity of the purified enzyme were measured by the quantitative electrophoresis method (17), using plasmid DNA, pBR322 or pUB110, as substrates and expressed as the 50% inhibitory concentrations (IC50s). The IC50s of ofloxacin, DR-3355 (l-ofloxacin), ciprofloxacin, tosufloxacin, sparfloxacin, and DS-4524, a new quinolone derivative, for pBR322 were 63.0, 37.8, 30.5, 46.0, 28.5, and 3.2 micrograms/ml, respectively. These values were closely correlated with antibacterial activity (MIC), with correlation coefficients of 0.953 for pBR322 and 0.938 for pUB110. These results indicate that, in S. aureus, as in gram-negative bacteria, DNA gyrase is likely to be a major target enzyme of quinolones.
In vitro activity of loracarbef (LY163892), a new oral carbacephem antimicrobial agent, against respiratory isolates of Haemophilus influenzae and Moraxella catarrhalis
Authors: Doern G V , Vautour R , Parker D , Tubert T , Torres B
Published: June 2012

The in vitro activity of a new orally administered carbacephem analog of cefaclor, loracarbef (LY163892), was compared with those of cefaclor and several other oral antimicrobial agents against recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis. Loracarbef was found to be slightly more active than cefaclor against H. influenzae and had activity essentially equivalent to that of cefaclor for M. catarrhalis. Resistance to loracarbef was uncommon and was noted only with rare beta-lactamase-producing strains of H. influenzae. On the basis of these observations, loracarbef may be of utility in the management of localized, non-life-threatening infections caused by H. influenzae and M. catarrhalis.
Inhibition of Cryptosporidium parvum in neonatal Hsd:(ICR)BR Swiss miceby polyether ionophores and aromatic amidines
Authors: Blagburn B L , Sundermann C A , Lindsay D S , Hall J E , Tidwell R R
Published: June 2012

Cryptosporidicidal effects of two polyether ionophores (maduramicin and alborixin), a fluorinated 4-quinolone (enrofloxacin), and three analogs of pentamidine were evaluated in a suckling mouse bioassay. Treatment with all compounds except enrofloxacin and one of the pentamidine analogs [1,3-di(4-imidazolinophenoxy)propane] resulted in significant (P less than 0.05) reductions in oocyst excretion.
Physiological effects of fenpropimorph on wild-type Saccharomyces cerevisiae and fenpropimorph-resistant mutants
Authors: Lorenz R T , Parks L W
Published: June 2012

Fenpropimorph-resistant mutants of Saccharomyces cerevisiae were isolated by a gradient selection procedure. The mutants were cross-resistant to other morpholines (fenpropidin, dodemorph, tridemorph) and 15-azasterol, but were susceptible to azoles (miconazole, clotrimazole, ketoconazole) and nystatin. In the absence of fenpropimorph, the major sterol produced by the mutants and the parental strain was ergosterol. In the presence of fenpropimorph, ignosterol (ergosta-8,14-dien-3 beta-ol) was the major sterol produced by the mutants and the parental strain. The resistance to fenpropimorph involves two recessive genes, each of which allows a semiresistance, when they are isolated apart from one another. Strain JR4 (erg3 erg11), which produces 14-methylfecosterol [14 alpha-methyl-ergosta-8,24(28)-dien- 3-beta-ol) as the major sterol in the presence or absence of fenpropimorph, was also found to be resistant to the drug. The growth inhibitory effect of fenpropimorph on wild-type cells appears to be linked to the production of ignosterol. The uptake of exogenous sterol by wild-type cells was greatly enhanced in the presence of fenpropimorph. The growth inhibition caused by fenpropimorph could only be overcome with bulk levels of exogenous C-5,6-unsaturated sterols.
Synergistic activity of 5-trifluoromethylthioribose and inhibitors of methionine synthesis against Klebsiella pneumoniae
Authors: Tower P A , Johnson L L , Ferro A J , Fitchen J H , Riscoe M K
Published: June 2012

5-Methylthioribose (MTR) is an intermediate in the methionine recycling pathway of organisms containing the enzyme MTR kinase. Analogs of MTR have been proposed as a new class of antimicrobial agents because of their ability to perturb the growth of MTR kinase-containing pathogens through inhibition of methionine salvage or by conversion to toxic products. One such analog, 5-trifluoromethylthioribose (TFMTR), has demonstrated potent inhibitory effects on the growth of Klebsiella pneumoniae (A. G. Gianotti, P. A. Tower, J. H. Sheley, P. A. Conte, C. Spiro, J. H. Fitchen, and M. K. Riscoe, J. Biol. Chem. 265:831-837, 1990). Although the mode of action of TFMTR has yet to be determined, it is believed that the drug is converted to the toxic products trifluoromethionine or carbonothioic difluoride via MTR kinase and the methionine recycling pathway. On the basis of this assumption, we theorized that blocking de novo methionine synthesis would increase dependence on the methionine salvage pathway and lead to an increased rate of synthesis of toxic metabolites from TFMTR. In this report, we show that three separate inhibitors of de novo methionine synthesis (1,2,4-triazole, azaserine, and propargylglycine) act synergistically with TFMTR in inhibiting the growth of K. pneumoniae.
Ofloxacin pharmacokinetics in mechanically ventilated patients
Authors: Martin C , Lambert D , Bruguerolle B , Saux P , Freney J , Fleurette J , Meugnier H , Gouin F
Published: June 2012

The pharmacokinetics of ofloxacin were studied in 12 intensive care patients, 6 of whom were under controlled mechanical ventilation. All patients had a creatinine clearance of greater than 80 ml/min per 1.73 m2. They were given 3 mg of ofloxacin per kg of body weight intravenously at a constant flow rate in 30 min twice a day for 7 days. Pharmacokinetic studies were performed on days 1 and 7. Between days 1 and 7, significant increases in the alpha (distribution) and beta (elimination) phase half-lives, the area under the serum concentration-time curve, and peak and trough levels in serum were observed, together with a marked decrease (greater than 50%) in total body clearance. Possible contributing factors for alteration of ofloxacin pharmacokinetics in ventilated patients were patient age, liver dysfunction, drug interaction, and drug accumulation in a deep compartment. This study shows that in intensive care patients the pharmacokinetics of ofloxacin differ from those reported for healthy volunteers.
Clinical evaluation of teicoplanin fluorescence polarization immunoassay
Authors: Rybak M J , Bailey E M , Reddy V N
Published: June 2012

A teicoplanin fluorescence polarization immunoassay (FPIA) developed by International BioClinical (IBC) was evaluated by using serum samples from patients who had been receiving teicoplanin at Detroit Receiving Hospital (DRH) as part of a clinical investigation. Patient samples collected over a 1-year span were assayed at DRH and at IBC, and the results were compared with those of a standard microbiological assay performed at Merrell Dow Research Institute, Indianapolis, Ind. The FPIA has a rapid turnaround time (circa 20 min), utilizes small sample volumes (less than 100 microliters) and is sensitive and accurate in determining concentrations in the range of 5 to 100 micrograms/ml. The intra-assay and interassay coefficient of variation for controls (7, 35, and 75 micrograms/ml) was less than or equal to 13%. Concentrations greater than 100 micrograms/ml must be diluted prior to the assay, which may introduce additional error in determination. The FPIA compared well with the bioassay (r = 0.901) for 193 clinical samples. The results obtained utilizing the FPIA system were reproducible at two different sites, as illustrated by the high degree of correlation between the results at DRH and IBC (r = 0.92). There was less than 7% interference noted when teicoplanin was assayed in the presence of other antibiotics. Patient samples stored for up to 1 year retained their potency: the mean recovery rate in these samples was 107%. The FPIA should be useful for monitoring and adjusting teicoplanin dosage regimens in patients.
Bacteremia caused by hemolytic, high-level gentamicin-resistant Enterococcus faecalis
Authors: Huycke M M , Spiegel C A , Gilmore M S
Published: June 2012

Between 1 January 1984 and 31 December 1987, 206 enterococcal blood isolates at the University of Wisconsin Hospital and Clinics were analyzed for high-level aminoglycoside resistance (hereafter high-level aminoglycoside resistance is simply referred to as "resistance") and hemolysin production. Of 190 Enterococcus faecalis isolates, 68 (35.8%) were resistant to gentamicin. Of these 68 strains, 67 (98.5%) contained a gene coding for the bifunctional aminoglycoside-modifying 6'-aminoglycoside acetyltransferase-2"-aminoglycoside phosphotransferase [AAC(6')-APH(2")] enzyme. Of 190 isolates, 85 (44.7%) were hemolytic and contained a gene coding for component A of the enterococcal hemolysin. Sixty-two of 68 (91.2%) gentamicin-resistant isolates but only 23 of 122 (18.8%) gentamicin-susceptible isolates were hemolytic (P less than 0.001). Twelve of the hemolytic, gentamicin-resistant E. faecalis blood isolates, but only 2 of 9 nonhemolytic or gentamicin-susceptible isolates, had identical chromosomal DNA restriction endonuclease digestion patterns, suggesting a common derivation for these strains. A historical cohort study from 1 July 1985 to 31 March 1987 identified by regression analysis postsurgical intensive care unit status (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.1 to 22.8) and prior treatment with an expanded- or broad-spectrum cephalosporin (OR, 3.0; 95% CI, 0.9 to 10.1) as risk factors for gentamicin-resistant E. faecalis bacteremia. Patients with hemolytic, gentamicin-resistant E. faecalis bacteremia had a fivefold-increased risk for death within 3 weeks of their bacteremia compared with patients with nonhemolytic, gentamicin-susceptible strains (95% CI, 1.0 to 25.4).
Pseudomonas pseudomallei resistance to beta-lactam antibiotics due to alterations in the chromosomally encoded beta-lactamase
Authors: Godfrey A J , Wong S , Dance D A , Chaowagul W , Bryan L E
Published: June 2012

Pseudomonas pseudomallei, the causative agent of melioidosis, is generally susceptible to some of the newer extended-spectrum cephalosporins or to combinations of a beta-lactam and clavulanic acid, a beta-lactamase inhibitor. Resistance to these agents may, however, emerge during treatment. We report on alterations in the chromosomal beta-lactamase associated with the development of resistance. Three resistance patterns resulted from three different mechanisms in the strains investigated. Derepression of the chromosomal enzyme resulted in a general increase in the MICs of all of the beta-lactams tested. The second mechanism observed was an insensitivity to inhibition of the beta-lactamase by clavulanic acid. In this case, the level of susceptibility to beta-lactams as independent entities remained unchanged. The final "resistance" pattern occurred in a patient treated with ceftazidime and resulted in a beta-lactamase that was capable of hydrolyzing this antibiotic at detectable levels, but with reduced efficacy against other beta-lactams. The net result was a strain that was generally susceptible to all of the beta-lactams tested except ceftazidime. In all cases, the level of susceptibility to antibiotics other than beta-lactams remained unchanged. Such variability found within one genus over a relatively short time course suggests that treatment of infections caused by this organism should be carefully monitored to detect susceptibility alterations to the chosen therapy.
Fluconazole susceptibility testing of Candida albicans: microtiter method that is independent of inoculum size, temperature, and time of reading
Authors: Anaissie E , Paetznick V , Bodey G P
Published: June 2012

In vitro antifungal susceptibility testing generally remains unstandardized and unreliable for directing therapy. When azoles are tested, this problem is further compounded by the lack of definite reading end points. We determined the in vitro susceptibility of 50 Candida albicans isolates (including 10 reference strains) to fluconazole by using a microbroth dilution method in which microtiter plates were agitated immediately before reading. Six fungal inoculum sizes (ranging from 2 x 10(2) to 4 x 10(5) CFU/ml), three different times of reading (24, 48, and 72 h), and two temperatures (30 and 35 degrees C) were tested. We also compared visual and spectrophotometric determinations of MIC end points. This agitation method resulted in clear-cut visual end points that were reproducible for different observers within the same laboratory, that were independent of inoculum size, temperature of incubation, and time of reading, and that correlated well with the degree of fungal inhibition as determined by spectrophotometry. Median MICs also correlated with usually achievable levels of fluconazole in serum and tissue of humans and experimental animals.
Isoniazid protects mice against endotoxin lethality without influencing tumor necrosis factor synthesis and release
Authors: Urbaschek R , Männel D N , Urbanczik R
Published: June 2012

Treatment of NMRI mice with isoniazid (INH; 25 mg/kg) intraperitoneally induced significant protection when it was injected before or after a lethal intravenous challenge with endotoxin. The INH preparation used was not contaminated with endotoxin. Tumor necrosis factor (TNF) was not elevated in sera from NMRI mice 2 h after the injection of INH. INH did not influence TNF synthesis or release determined in human monocytes in vitro. Therefore, it is concluded that the protective effect of INH against lethal endotoxin is not due to a suppressive effect of INH on TNF production.
Antibody responses to in vitro translation products following albendazole therapy for Echinococcus granulosus
Authors: Blanton R E , Okelo G B , Kijobe J , King C H
Published: June 2012

Immunoprecipitation of antigens translated in vitro from Echinococcus granulosus RNA revealed that albendazole treatment of human hydatidosis induced antibodies to previously undetectable antigens and that the response to most antigens was specific, although cross-reactivity was observed between Schistosoma mansoni and E. granulosus antisera for two proteins.
Effect of pH on the in vitro potency of clarithromycin against Mycobacterium avium complex
Authors: Truffot-Pernot C , Ji B , Grosset J
Published: June 2012

Employing 7H11 agar medium at pH 6.6, the MICs of clarithromycin for 50% (MIC50) and 90% (MIC90) of 19 strains of Mycobacterium avium complex were 8 and 16 micrograms/ml, respectively. However, the MICs were 2 to 3 log2 dilutions lower in the 7H11 medium adjusted to pH 7.4, and the MICs on 10% OADC (oleic acid-albumin-dextrose-catalase)-enriched Mueller-Hinton agar at pH 7.3 were also 2 log2 dilutions lower than those measured on 7H11 agar at pH 6.6. Therefore, clarithromycin is more active at a physiologic than at an acidic pH.
Comparison of single-dose administration and three-day course of amoxicillin with those of clavulanic acid for treatment of uncomplicated urinary tract infection in women
Authors: Raz R , Rottensterich E , Boger S , Potasman I
Published: June 2012

In a double-blind randomized study we compared a single-dose amoxicillin-clavulanate combination with a regular 3-day regimen in 109 women with cystitis. Clinical cure rates at 7 and 28 days posttreatment were 78 versus 87% and 67 versus 78%, respectively. The 3-day regimen was significantly better (P less than 0.001) only in women with recurrent urinary tract infections.
Pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis and Staphylococcus aureus demonstrated by studies of initial killing and postantibiotic effect and influence of Ca2+ and albumin on these drugs
Authors: Hanberger H , Nilsson L E , Maller R , Isaksson B
Published: June 2012

The pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 25923 were investigated by studying the postantibiotic effect (PAE) and initial killing. The influence of Ca2+ and albumin on these drugs was also evaluated. The PAE was studied by use of bioluminescence assay of bacterial ATP. Daptomycin at clinically achievable concentrations produced a dose-dependent PAE on E. faecalis (0.6 to 6.7 h) and S. aureus (1.0 to 6.3 h). The long PAE of daptomycin was seen simultaneously with a potent dose-dependent initial killing assayed by viable count determination. The initial change in bacterial ATP was not as extensive as the decrease in viability. Vancomycin at corresponding concentrations produced shorter PAEs on E. faecalis (0.5 to 1.0 h) and S. aureus (1.3 to 1.8 h). This coincides with a weak non-dose-dependent initial change in viability and intracellular ATP. The MICs of vancomycin were not influenced by different Ca2+ concentrations or by the addition of albumin to the broth. The MICs of daptomycin for both strains were lowered, and the PAEs were prolonged with increasing concentrations of Ca2+ in the broth. The PAE of daptomycin was Ca2+ dependent to the same extent as the MIC was. In the presence of physiological concentrations of albumin and free Ca2+, the PAEs of daptomycin on both strains were reduced and the MICs were increased in comparison with the results obtained in pure Mueller-Hinton broth with approximately the same free Ca2+ concentration. This decrease in daptomycin activity was considered to be due to the albumin binding of daptomycin. Despite the albumin binding of daptomycin, the PAE produced on E. faecalis and S. aureus in the presence of a physiological free Ca2+ concentration was still over 6 h at clinically achievable concentrations.
Pharmacokinetics and renal tolerance of aztreonam in premature infants
Authors: Cuzzolin L , Fanos V , Zambreri D , Padovani E M , Benoni G
Published: June 2012

Aztreonam (30 mg/kg of body weight) was administered intravenously over 3 min every 12 h to 30 preterm neonates divided into two groups according to gestational age (mean age for group A was less than 30 weeks and mean age for group B was greater than 30 weeks) and birth weight (mean weight for group A was less than 1,500 g and mean weight for group B was greater than 1,500 g). Blood and urine samples were analyzed by microbiological assay. The pharmacokinetics were described by one-compartment and noncompartment models. The mean half-life and clearance for premature infants weighing less than 1,500 g were 5.33 +/- 3.61 h and 1.52 +/- 1.33 ml/min/kg, respectively; for those weighing more than 1,500 g, the values were 4.08 +/- 2.28 h and 2.41 +/- 2.10 ml/min/kg, respectively. The mean urinary concentration of aztreonam in 15 premature infants during the first 6 h of therapy was 242.72 +/- 188.19 micrograms/ml, with a mean percentage of elimination of 13.29%. Urinary excretion of N-acetyl-beta-D-glucosaminidase (a specific and sensitive test for the detection of drug-induced renal tubule damage) did not show significant differences in our group of premature infants compared with that in a control group. The dose of 30 mg/kg and a dosage interval of 8 to 12 h could be recommended for the treatment of suitable bacterial infections in all premature infants.
Nucleotide sequence of the beta-lactamase gene from Enterococcus faecalis HH22 and its similarity to staphylococcal beta-lactamase genes
Authors: Zscheck K K , Murray B E
Published: June 2012

The nucleotide sequence of the constitutively produced beta-lactamase (Bla) gene from Enterococcus faecalis HH22 was shown to be identical to the published sequences of three of four staphylococcal type A beta-lactamase genes; more differences were seen with the genes for staphylococcal type C and D enzymes. One hundred forty nucleotides upstream of the beta-lactamase start codon were determined for an inducible staphylococcal beta-lactamase and were identical to those of the constitutively expressed enterococcal gene, indicating that the changes resulting in constitutive expression are not due to changes in the promoter or operator region. Moreover, complementation studies indicated that production of the enterococcal enzyme could be repressed. The genes for the enterococcal Bla and an inducible staphylococcal Bla were each cloned into a shuttle vector and transformed into enterococcal and staphylococcal recipients. The major difference between the backgrounds of the two hosts was that more enzyme was produced by the staphylococcal host, regardless of the source of the gene. The location of the enzyme was found to be host dependent, since each cloned gene generated extracellular (free) enzyme in the staphylococcus and cell-bound enzyme in the enterococcus. On the basis of the identities of the enterococcal Bla and several staphylococcal Bla sequences, these data suggest the recent spread of beta-lactamase to enterococci and also suggest the loss of a functional repressor.
Effects of ranitidine and sucralfate on ketoconazole bioavailability
Authors: Piscitelli S C , Goss T F , Wilton J H , D'Andrea D T , Goldstein H , Schentag J J
Published: June 2012

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P less than 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.
Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection
Authors: Lemaitre B C , Mazigh D A , Scavizzi M R
Published: June 2012

The treatment of yersiniosis by beta-lactams is questionable considering the proven failure of newer beta-lactams for treating murine Yersinia enterocolitica infection. Another modality of experimental treatment was performed with a virulent strain of Y. pseudotuberculosis (nonproducer of beta-lactamase) highly susceptible (in terms of MICs) to amoxicillin, cefotaxime, ceftriaxone, imipenem, doxycycline, gentamicin, and ofloxacin. The in vivo comparative efficacy of these drugs was evaluated in a standardized and reproducible mouse model of systemic infection. Each single antibiotic was injected intravenously once, at 30 h after intravenous inoculation of the infective strain, and then repeatedly (at 30, 52, and 76 h postinfection). In vivo results were measured by counting the viable bacteria recovered from the whole spleens of mice sacrificed at selected times. Cefotaxime, even at high doses (250 mg/kg of body weight), was totally ineffective. Amoxicillin and imipenem at high doses (200 and 100 mg/kg, respectively) and ceftriaxone at usual doses (20 mg/kg) were active only in stopping bacterial proliferation to a more or less slight degree. Ceftriaxone was able to reduce viable counts in the spleen only at high doses (200 mg/kg), as were gentamicin (20 mg/kg) and doxycycline (125 mg/kg). Ofloxacin at the low dose of 5 mg/kg was demonstrated to be very effective by the very significant decrease observed in bacterial numbers from 10(6) to 10(3) CFU per spleen. The pharmacological parameters do not in themselves explain all the discrepancies between the in vitro and in vivo activities of beta-lactams on yersiniae. No emergence of beta-lactam-resistant organisms, which could explain the failure of beta-lactams, was detected. Thus, their use should be delayed in the therapy of human yersinosis until further investigations are carried out. The fluoroquinolone appeared more active and rapid than reference drugs in the treatment of murine yersinosis, which confirms initial clinical results.
Use of ciprofloxacin versus use of aminoglycosides for therapy of complicated urinary tract infection: prospective, randomized clinical and pharmacokinetic study
Authors: Fang G D , Brennen C , Wagener M , Swanson D , Hilf M , Zadecky L , DeVine J , Yu V L
Published: June 2012

The efficacy of oral ciprofloxacin was compared with that of parenteral aminoglycoside for therapy of complicated urinary tract infection in a prospective randomized trial. The setting was a chronic-care Veterans Administration facility in which long-term bladder catheterization and resistant bacteria were common. Sixty-five consecutive patients were stratified for presence and type of bladder catheter, the presence of Providencia and Pseudomonas aeruginosa organisms versus other urinary pathogens, and renal dysfunction. A pharmacokinetic study of ciprofloxacin concentrations in serum and urine was performed with selected patients. Urinary catheters were present in 94%. All patients were symptomatic, and 58.5% had fever. Ciprofloxacin, 500 mg every 12 h orally, was compared with parenteral aminoglycoside for 7 to 10 days. Clinical response, defined by resolution of symptoms and fever at 5 to 9 days posttherapy (short-term) and 28 to 30 days posttherapy (long-term), was essentially identical for both treatment groups. Bacteriologic response, defined by sterile urine cultures, showed that ciprofloxacin was significantly more efficacious (P = 0.0005) than aminoglycoside at 5 to 9 days posttherapy. However, by 28 to 30 days, the response rate was essentially identical. Emergence of resistance to the study antibiotic was seen in 62 and 70% of those who did not show a bacteriological response and were receiving ciprofloxacin and aminoglycosides, respectively. Concentrations of ciprofloxacin and aminoglycoside in the urine substantially exceeded the MIC for the urinary pathogens isolated, although these concentrations did not correlate with short-term bacteriologic response for either antibiotic. Ciprofloxacin was efficacious in complicated urinary tract infection compared with the current standard of parenteral aminoglycoside among catheterized patients with relatively resistant bacteria.
Comparison of the inoculum effect of cefoxitin and other cephalosporins and of beta-lactamase inhibitors and their penicillin-derived components on the Bacteroides fragilis group
Authors: Goldstein E J , Citron D M , Cherubin C E
Published: June 2012

We compared the inoculum effects for 109 recent clinical isolates of the Bacteroides fragilis group of cefoxitin, cefotetan, ceftizoxime, ceftriaxone, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. Ceftizoxime demonstrated the largest inoculum effect, followed by cefotetan and ceftriaxone. The large inoculum effect of ceftizoxime and ceftriaxone was correlated with filamentous transformation at the high inoculum (10(8) CFU/ml) and lack of bactericidal activity suggesting drug destruction or inactivation. Cefotetan was bactericidal for B. fragilis isolates but not for other members of the B. fragilis group. Cefoxitin showed the least inoculum effect and was consistently bactericidal at high (10(8) CFU/ml), standard (10(6) CFU/ml), and low (10(4) CFU/ml) inocula, followed by ampicillin-sulbactam. Piperacillin-tazobactam and ticarcillin-clavulanic acid showed an intermediate inoculum effect. The degree of inoculum effect observed generally correlated with bactericidal activity at all inocula.
Appearance of a new trimethoprim resistance gene, dhfrIX, in Escherichia coli from swine
Authors: Jansson C , Sköld O
Published: June 2012

A new gene, dhfrIX, coding for a trimethoprim-resistant dihydrofolate reductase (DHFR), was found in porcine isolates of Escherichia coli. The new enzyme, DHFR IX, containing 178 amino acids, showed an amino acid similarity of about 26% with DHFR I and the chromosomal DHFR of E. coli K-12. The dhfrIX gene was observed to occur on two distinctly different transferable plasmids, although a fragment of about 2.9 kb, including dhfrIX, had an identical restriction enzyme digestion map in each case. The new plasmid-borne dhfrIX gene mediates resistance to a drug level of only about 250 micrograms/ml, as compared with more than 1,000 micrograms/ml for the more frequently encountered dhfrI gene. The new plasmid-borne trimethoprim resistance gene could have been selected and spread as a consequence of the extensive use of trimethoprim in veterinary practice in Sweden. It will be important to try to follow its possible occurrence in human pathogens as well.
Integration of pharmacokinetics and pharmacodynamics of imipenem in a human-adapted mouse model
Authors: Flückiger U , Segessenmann C , Gerber A U
Published: June 2012

The relationship between the pharmacokinetics and bactericidal activity of imipenem against Pseudomonas aeruginosa and Escherichia coli was investigated in a neutropenic mouse thigh infection model. To circumvent the problem of short elimination time in small animals, imipenem was administered in fractionized, decreasing doses such that the pharmacokinetic profiles as observed in humans after intravenous and intramuscular injections were approximated in mice. The human-simulated kinetic profile corresponding to an intramuscular injection of 500 mg at 12-h intervals proved to be as effective as the human-simulated profile of the same dose injected intravenously every 6 h. In contrast, the human-simulated profile corresponding to only one intravenous injection every 12 h resulted in bacterial breakthrough growth between 8 and 12 h after the onset of treatment. The results of our investigations confirm the hypothesis that the bactericidal effect of imipenem against P. aeruginosa and E. coli in vivo depends mainly on the time during which drug levels remain above the MIC rather than on the plasma peak/MIC ratio.
Comparison of cefprozil and cefaclor for treatment of acute urinary tract infections in women
Authors: Iravani A
Published: June 2012

A total of 108 college women with acute urinary tract infections were treated for 10 days with either 500 mg of cefprozil (BMY-28100-03-800) once a day (n = 72) or 250 mg of cefaclor three times a day (n = 36). Clinical and bacterial cure rates at 1 week posttherapy were 94 and 93%, respectively, for the cefprozil group and 94 and 94%, respectively, for the cefaclor group (P, not significant). Both cefprozil and cefaclor were safe and effective.
Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine
Authors: Fitzgibbon J E , Howell R M , Haberzettl C A , Sperber S J , Gocke D J , Dubin D T
Published: June 2012

To investigate whether human immunodeficiency virus type 1 pol gene mutations are selected during prolonged 2',3'-dideoxycytidine (ddC) therapy, we used the polymerase chain reaction to amplify a portion of the reverse transcriptase segment of the pol gene from the peripheral blood mononuclear cell DNA of a patient with AIDS before and after an 80-week course of ddC therapy. The consensus sequence from the second sample contained a unique double mutation (ACT to GAT) in the codon for reverse transcriptase amino acid 69, causing substitution of aspartic acid (Asp) for the wild-type threonine (Thr). A mutation (ACA to ATA) also occurred in the codon for position 165, causing substitution of isoleucine (Ile) for Thr. The GAT (Asp) codon was introduced into the pol gene of a molecular clone of human immunodeficiency virus via site-directed mutagenesis. Following transfection, mutant and wild-type viruses were tested for susceptibility to ddC by a plaque reduction assay. The mutant virus was fivefold less susceptible to ddC than the wild type; cross-resistance to 3'-azido-3'-deoxythymidine or 2'3'-dideoxyinosine was not found. The Ile-165 mutation did not confer additional ddC resistance. The Asp-69 substitution may have contributed to the generation of resistant virus in this patient.