bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers
Authors: Nakashima M , Uematsu T , Kosuge K , Umemura K , Hakusui H , Tanaka M
Published: June 2012

The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.
Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers
Authors: Peck R W , Weatherley B C , Wootton R , Crome P , Holdich T A , Posner J
Published: June 2012

882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 microM, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 microM.h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least 5 h after dosing with 882C87 before 5PU was detectable in plasma.
Nikkomycin Z supersensitivity of an echinocandin-resistant mutant of Saccharomyces cerevisiae
Authors: el-Sherbeini M , Clemas J A
Published: June 2012

Echinocandins and nikkomycins are antibiotics that inhibit the synthesis of the essential cell wall polysaccharide polymers 1,3-beta-glucan and chitin, respectively. Some 40 echinocandin-resistant Saccharomyces cerevisiae mutants were isolated and assigned to five complementation groups. Four complementation groups contained mutants with 38 recessive mutations. The fifth complementation group comprised mutants with one dominant mutation, etg1-3 (strain MS10), and one semidominant mutation, etg1-4 (strain MS14). MS10 and MS14 are resistant to the semisynthetic pneumocandin B, L-733,560, and to aculeacin A but not to papulacandin. In addition, microsomal membranes of both mutant strains contain 1,3-beta-glucan synthase activity that is resistant to L-733,560 but not to papulacandin. Furthermore, MS14 is also supersensitive to nikkomycin Z. The echinocandin resistance and the nikkomycin Z supersensitivity of MS14 cosegregated in genetic crosses. The wild-type gene (designated ETG1 [C. Douglas, J. A. Marrinan, and M. B. Kurtz, J. Bacteriol. 176:5686-5696, 1994, and C. Douglas, F. Foor, J. A. Marrinan, N. Morin, J. B. Nielsen, A. Dahl, P. Mazur, W. Baginsky, W. Li, M. El-Sherbeini, J. A. Clemas, S. Mandala, B. R. Frommer, and M. B. Kurtz, Proc. Natl. Acad. Sci. USA, in press]) was isolated from a genomic library in the plasmid YCp50 by functional complementation of the nikkomycin Z supersensitivity phenotype. The cloned DNA also partially complements the echinocandin resistance phenotype, indicating that the two phenotypes are due to single mutations. The existence of a single mutation, in MS14, simultaneously affecting sensitivity to a glucan synthase inhibitor and a chitin synthase inhibitor implies a possible interaction between the two polymers at the cell surface.
Antimicrobial susceptibilities of Corynebacterium species and other non-spore-forming gram-positive bacilli to 18 antimicrobial agents
Authors: Soriano F , Zapardiel J , Nieto E
Published: June 2012

The susceptibilities of 265 strains of Corynebacterium species and other non-spore-forming gram-positive bacilli to 18 antimicrobial agents were tested. Most strains were susceptible to vancomycin, doxycycline, and fusidic acid. Corynebacterium jeikeium and Corynebacterium urealyticum were the most resistant organisms tested. Resistance to beta-lactams, clindamycin, erythromycin, azythromycin, ciprofloxacin and gentamicin was common among strains of Corynebacterium xerosis and Corynebacterium minutissimum. Ampicillin resistance among Listeria monocytogenes was more prevalent than previously reported. Optochin, fosfomycin, and nitrofurantoin showed very little activity against most organisms tested, but the use of nitrofurantoin as a selective agent in culture medium may prevent the recovery of some isolates. Except for the unvarying activity of vancomycin against Corynebacterium species, the antimicrobial susceptibilities of the latter to other antibiotics are usually unpredictable, such that susceptibility tests are necessary for selecting the best antimicrobial treatment.
Survey of in vitro susceptibilities of Vibrio cholerae O1 and O139 to antimicrobial agents
Authors: Yamamoto T , Nair G B , Albert M J , Parodi C C , Takeda Y
Published: June 2012

Vibrio cholerae O139 (173 strains) and O1 (221 strains) were tested for their in vitro susceptibilities to 39 antimicrobial agents. Both O139 and O1 strains were highly susceptible to azithromycin, cephems, minocycline, penems, and newer fluoroquinolones. O139 strains (94.8%), O1 Indian El Tor strains (97%), and Bangladeshi El Tor strains (50%) were highly resistant to streptomycin, sulfamethoxazole, and trimethoprim and moderately resistant to chloramphenicol and furazolidone, in sharp contrast to O1 Peruvian El Tor and O1 classical strains. Some Bangladeshi El Tor strains (43.3%) showed tetracycline resistance as well.
In vivo correlates for Streptococcus pneumoniae penicillin resistance in acute otitis media
Authors: Gehanno P , Lenoir G , Berche P
Published: June 2012

Eighty-four children suffering from acute otitis media caused by Streptococcus pneumoniae were treated prospectively with cefuroxime axetil suspension (30 mg/kg of body weight twice daily for 8 days). The high incidence of isolates with decreased susceptibilities to penicillin (42 of 84 isolates) allowed us to establish a relationship between clinical success and the penicillin MICs for pneumococcal isolates. It was found that cefuroxime axetil is clinically effective in the treatment of acute otitis media caused by penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The results indicate that the risk of treatment failure with cefuroxime axetil was increased in children with otitis media caused by S. pneumoniae when the penicillin MIC were greater than or equal to 2 mg/liter.
Effect of food on absorption of cefpodoxime proxetil oral suspension in adults
Authors: Borin M T , Forbes K K
Published: June 2012

The effect of a high-fat meal on absorption of a 200-mg dose of cefpodoxime proxetil oral suspension was evaluated in 20 healthy, male volunteers in a randomized, two-way crossover study. The concentrations of cefpodoxime in plasma and in urine were determined by sensitive and specific high-performance liquid chromatography methods. The area under the plasma drug concentration-time curve, time to peak concentration, and urinary excretion of cefpodoxime were significantly greater (P < or = 0.05) after administration of cefpodoxime proxetil oral suspension with food than under fasting conditions. However, the difference in the areas under the curve between fed and fasted treatments was only 11%, and application of the two one-sided tests procedure showed bioequivalence between treatments for this parameter. The slight increase in the extent of drug absorption and the slower rate of absorption which results when cefpodoxime proxetil is given with food are unlikely to be of clinical importance.
Pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients
Authors: Chin T W , Vandenbroucke A , Fong I W
Published: June 2012

Current dosage regimens of trimethoprim-sulfamethoxazole used to treat Pneumocystis carinii pneumonia in AIDS patients have been based on data from healthy subjects or patients without AIDS. The clearance and absorption characteristics of the drugs may potentially be different between patients with and without AIDS. This study was conducted to assess the pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients treated for P. carinii pneumonia. Patients received trimethoprim at 15 mg/kg of body weight and sulfamethoxazole at 75 mg/kg of body weight daily intravenously in three to four divided doses and were switched to the oral route when the regimen was tolerated. Serum samples for determination of drug concentrations were obtained over 12 h after intravenous and oral dosing. The pharmacokinetics of trimethoprim and sulfamethoxazole were compared in eight critically ill versus nine non-critically ill male patients and were as follows, respectively: clearance, 1.88 +/- 0.44 versus 1.73 +/- 0.64 ml/min/kg for trimethoprim and 0.40 +/- 0.12 versus 0.34 +/- 0.11 ml/min/kg for sulfamethoxazole; volume of distribution, 1.6 +/- 0.5 versus 1.5 +/- 0.5 liters/kg for trimethoprim and 0.5 +/- 0.3 versus 0.4 +/- 0.1 liters/kg for sulfamethoxazole; and half-life, 10.9 +/- 7.4 versus 11.3 +/- 4.0 h for trimethoprim, and 15.5 +/- 9.5 versus 14.3 +/- 4.7 h for sulfamethoxazole. No significant differences (P > 0.05) were observed between patient groups, although there was wide intersubject variability. Absorption appeared to be similar between the critically ill and non-critically patients: bioavailability was 97.5% +/- 22.4% versus 101.8% +/- 22.7% for trimethoprim and 86.2% +/- 17.9% versus 99.1% +/- 20.5% for sulfamethoxazole, respectively. Because of the similar pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients, the two groups of patients may receive similar dosages. Dosage adjustment does not appear to be required when switching from the intravenous to the oral route.
Antifungal susceptibility testing of isolates from a randomized, multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia. NIAID Mycoses Study Group and the Candidemia Study Group
Authors: Rex J H , Pfaller M A , Barry A L , Nelson P W , Webb C D
Published: June 2012

The antifungal susceptibilities of 232 pathogenic blood stream Candida isolates collected during a recently completed trial comparing fluconazole (400 mg/day) with amphotericin B (0.5 mg/kg of body weight per day) as treatment for candidemia in the nonneutropenic patient were determined both by the National committee for Clinical Laboratory Standards M27-P macrobroth methodology and by a less cumbersome broth microdilution methodology. For amphotericin B, M27-P yielded a very narrow range of MICs (0.125 to 1 microgram/ml) and there were no susceptibility differences among species. For fluconazole, a broad range of MICs were seen (0.125 to > 64 micrograms/ml), with characteristic MICs seen for each species in the rank order Candida albicans < C. parapsilosis approximately equal to C. lusitaniae < C. glabrata approximately equal to C. krusei approximately equal to C. lipolytica. The MIC distribution for C. tropicalis was bimodal and could not be ranked. Both microdilution MICs were within one tube dilution of the M27-P MIC for > 90% of isolates with amphotericin B and for > or = 77% of isolates with fluconazole. For both methods, elevated MICs did not predict treatment failure. In the case of amphotericin B, the MIC range was too narrow to permit identification of resistant isolates. In the case of fluconazole, MICs for isolates associated with failure to clear the bloodstream consistently were equivalent to the median MIC for the given species. Successful courses of therapy were seen with four isolates from four patients despite MICs of > or = 32 micrograms/ml. As MICs obtained by M27-P and similar methods correlate with responsiveness to fluconazole therapy in animal models and in AIDS patients with oropharyngeal candidiasis, the lack of correlation in this setting suggests that the MICs for these isolates are at or below the relevant fluconazole breakpoint for this dose of fluconazole and patient setting and that host factors such as failure to exchange intravenous catheters were more important than MIC in predicting outcome.
Long-chain alkanoylcholines, a new category of soft antimicrobial agents that are enzymatically degradable
Authors: Ahlström B , Chelminska-Bertilsson M , Thompson R A , Edebo L
Published: June 2012

A new category of amphiphilic hydrolyzable quaternary ammonium compounds with rapid and high levels of antimicrobial activity was studied. The compounds, alkanoylcholines with hydrocarbon chains of 10 to 14 carbon atoms, are hydrolyzed by butyrylcholine esterase, which is present in human serum and mucosal membranes. The hydrolysis products are common components of human metabolism. Alkanoylcholines were tested and found to be active against gram-negative and gram-positive bacteria as well as yeasts. The microbicidal activities of the alkanoylcholines were comparable to the activities of the stable quaternary ammonium compounds of corresponding chain length and increased with an increasing number of carbon atoms. The compounds were also found to be hydrolyzed by enzymes present in certain microorganisms. The degradation was achieved after reaching the microbicidal effect.
Chemoprophylaxis of Cryptosporidium parvum infection with paromomycin in kids and immunological study
Authors: Mancassola R , Reperant J M , Naciri M , Chartier C
Published: June 2012

The anticryptosporidial activity of paromomycin, a natural antibiotic weakly absorbed when administered per os, was assessed in goat kids experimentally infected once via the oral route with 10(6) Cryptosporidium parvum oocysts. Paromomycin used prophylactically at a dose of 100 mg/kg of body weight per day from day-1 to day 10 (day 0 was the inoculation day) prevented infection during the period of drug administration. A delayed low infection was suggested by an antibody rise, but the infection developed below the microscopic detection limits. This low parasite development induced a partial immunity in kids, which reacted immunologically to a challenge on day 21 without symptoms or detectable oocyst shedding. So, paromomycin is a good candidate for field trials because it is prophylactically effective against experimental C. parvum infection and well tolerated by animals. This drug would be useful in an adapted form as an anticryptosporidial agent for neonatal ruminants.
Comparison of concentrations of two doses of clavulanic acid (200 and 400 milligrams) administered with amoxicillin (2,000 milligrams) in tissues of patients undergoing colorectal surgery
Authors: Martin C , Mallet M N , Sastre B , Viviand X , Martin A , De Micco P , Gouin F
Published: June 2012

The concentrations of clavulanic acid and amoxicillin were determined in sera and different abdominal tissues of 17 patients who underwent elective colorectal surgery. Patients were randomly allocated to two groups. At the time of induction of anesthesia, patients in group 1 were given 200 mg of clavulanic acid with 2,000 mg of amoxicillin and patients in group 2 received 400 mg of clavulanic acid with 2,000 mg of amoxicillin. In both groups, the initial dose was administered again after 2 h. Blood samples were collected to determine peak and trough antibiotic levels. Serial blood samples were also collected at predetermined periods (opening and closure of the abdominal cavity and surgical anastomosis). Abdominal wall fat, epiploic fat, and colonic wall tissue samples were collected simultaneously. Antibiotic concentrations were determined by high-performance liquid chromatography. Increasing the dose of clavulanic acid to 400 mg resulted in significantly higher peak and trough levels in serum (P < 0.03). Following the injection of 400 mg, mean concentrations of clavulanic acid in the fatty tissues were significantly increased at the time of opening (P < 0.02). The concentrations of clavulanic acid and amoxicillin in fatty tissues were 17 to 52% and 12 to 23% of the levels in sera, respectively. In the colonic wall, the concentrations of clavulanic acid and amoxicillin were 52 to 63% and 49 and 27% of the levels in sera, respectively. In sera, clavulanic acid given at a dose of 200 or 400 mg reached or exceeded the concentrations found to be effective in vitro to reduce the MICs of amoxicillin from the resistant to the susceptible category for 90% of the potential pathogens. In most of the tissues investigated, increased the dose of clavulanic acid to 400 mg resulted in a significantly higher number of samples with concentrations found to be effective in vitro (72 versus 11%; P < 0.05). In conclusion, increasing the dose of clavulanic acid to 400 mg resulted in higher levels in sera and improved penetration into the abdominal tissues in patients undergoing colorectal surgery.
Antipneumocystis activity of 17C91, a prodrug of atovaquone
Authors: Comley J C , Yeates C L , Frend T J
Published: June 2012

The prophylactic efficacy of 17C91, a carbamate prodrug of atovaquone (ATQ), was investigated in a severe combined immunodeficient mouse model of Pneumocystis carinii pneumonia (PCP). At an oral dosage equivalent to 100 mg of ATQ per kg of body weight per day, 17C91 protected 9 of 10 mice from PCP and had a prophylactic efficacy comparable to that of co-trimoxazole (at 250 mg of sulfamethoxazole plus 50 mg of trimethoprim per kg per day orally). The intensity of P. carinii infection (infection score) of mice treated with 17C91 correlated with the concentration of ATQ in the plasma, with clearance of the infection associated with plasma ATQ levels of >35 micrograms/ml. 17C91 given orally provided enhanced levels of ATQ in the plasma compared with the conventional ATQ formulation. Additional studies reported in this paper demonstrate that the prophylactic activity of 17C91 against PCP in severe combined immunodeficient mice is comparable to that of a new oral microparticulate formulation of ATQ.
Vancomycin or vancomycin plus netilmicin for methicillin- and gentamicin-resistant Staphylococcus aureus aortic valve experimental endocarditis
Authors: Perdikaris G , Giamarellou H , Pefanis A , Donta I , Karayiannakos P
Published: June 2012

Using a rabbit model of aortic valve endocarditis, we studied the efficacy of vancomycin alone or in combination with netilmicin and/or rifampin against a methicillin- and gentamicin-resistant strain of Staphylococcus aureus (MGRSA). Antibiotics were given for 6 to 12 days, as follows: vancomycin (15 mg/kg of body weight every 12 h [BID] intravenously), vancomycin plus netilmicin (2.5 mg/kg BID intramuscularly), vancomycin plus rifampin (10 mg/kg BID intramuscularly), and vancomycin plus netilmicin plus rifampin at the same routes, dosages, and schedules mentioned above. Netilmicin was given to two additional groups at a higher dosage (6 mg/kg every 24 h intramuscularly) alone or in combination with vancomycin (15 mg/kg BID intravenously) for 12 days. All regimens resulted in undetectable bacterial counts in a significant proportion of vegetations (except netilmicin alone) or reduced the bacterial counts in the vegetations compared with the counts in the untreated controls (P<0.01 to P<0.001). No resistance to rifampin or netilmicin developed during therapy. It is concluded that in the treatment of experimental aortic valve endocarditis caused by MGRSA (i) vancomycin as monotherapy is as efficacious as the triple combination, (ii) the addition of netilmicin (once daily or BID) to vancomycin does not improve the efficacy of the latter antibiotic, even in the presence of rifampin, and (iii) a 12-day course in more effective than a 6-day one, but not at a statistically significant level.
Population pharmacokinetics of stavudine (d4T) in patients with AIDS or advanced AIDS-related complex
Authors: Horton C M , Dudley M N , Kaul S , Mayer K H , Squires K , Dunkle L , Anderson R
Published: June 2012

The population pharmacokinetics and bioavailability of oral stavudine (d4T; 2',3'-dideoxy-3'-deoxythymidine) was determined in 81 patients with AIDS or AIDS-related complex (ARC) enrolled in phase I and phase I/II dose-ranging trials. Each patient underwent inpatient pharmacokinetic studies following administration of the first oral stavudine dose; 59 patients were restudied after chronic therapy for an average of 19 days. Thirty-three of these patients also received a single intravenous stavudine dose prior to starting an oral regimen. A two-compartment model with first-order absorption and elimination was used as the structural pharmacokinetic model. A basic model provided the following population parameter estimates (interpatient variability expressed in parentheses as percent coefficient of variation): clearance/bioavailability = 30.9 (24.5%) liters/h; volume of distribution/bioavailability = 8.42 (not modeled) liters; volume of distribution at steady state/bioavailability = 68.9 (105%) liters; intercompartmental clearance/bioavailability = 12.4 (26%) liters/h; and first-order absorption rate constant = 1.32 (78.9%) liters/h. In the subset of 33 patients receiving both intravenous and oral doses, the bioavailability of stavudine was estimated to be 99.1% (18.5%). Total body weight, stage of disease (AIDS versus ARC), and an oral stavudine dose of > or = 200 mg were found to have a statistically significant but a clinically marginal effect on the estimate of the oral clearance of stavudine. This analysis shows the high degree of bioavailability of stavudine in patients with AIDS and ARC and the relatively low degree of interpatient variability in oral drug clearance compared with those of other nucleosides. Population pharmacokinetic analysis is a useful tool for assessing the combined effects of several patient variables on the pharmacokinetic properties of drugs in human immunodeficiency virus-infected patients.
Potent and specific inhibition of human immunodeficiency virus type 1 replication by 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-Y1 N,N-dialkylcarbamate derivatives
Authors: Ijichi K , Fujiwara M , Hanasaki Y , Watanabe H , Katsuura K , Takayama H , Shirakawa S , Sakai S , Shigeta S , Konno K
Published: June 2012

4-(2,6-Dichlorophenyl)-1,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives were found to be highly potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell cultures. The most potent congener of TDA derivatives, RD4-2024, inhibited HIV-1 replication by 50% at concentrations of 12.5 and 4.8 nM in MT-4 cells and peripheral blood mononuclear cells, respectively. These concentrations were more than 2,000- and 30,000-fold lower than its 50% cytotoxic concentrations, respectively. Although the TDA derivatives were active against 3'-azido-3'-deoxythymidine-resistant HIV-1, no antiviral activities were observed against HIV-2 and nonnucleoside reverse transcriptase inhibitor-resistant mutants of HIV-1. The TDA derivatives inhibited recombinant HIV-1 reverse transcriptase activity, depending on the template-primer used for the assay. However, they did not interact with HIV-2 reverse transcriptase. Thus, the TDA derivatives belong to the family of nonnucleoside reverse transcriptase inhibitors. Because of their potent anti-HIV-1 activities in vitro and their low levels of toxicity in mice, the TDA derivatives deserve further evaluation as candidate drugs for the treatment of patients with AIDS.
Emergence of in vitro resistance to fluoroquinolones in Neisseria gonorrhoeae isolated in Japan
Authors: Tanaka M , Matsumoto T , Kobayashi I , Uchino U , Kumazawa J
Published: June 2012

To investigate emerging fluoroquinolone resistance in Neisseria gonorrhoeae isolated in Japan, we compared the in vitro antimicrobial susceptibilities of 79 gonococcal isolates from 1992 through 1993 to 14 fluoroquinolones and 14 other antibiotics with those of 27 isolates from between 1981 and 1984. The MICs at which 90% of the isolates were inhibited by nine fluroquinolones, including norfloxacin, enoxacin, ofloxacin, ciprofloxacin, tosufloxacin, lomefloxacin, fleroxacin, levofloxacin, and sparfloxacin, for isolates from 1992 to 1993 were 8- or 16-fold higher than those for isolates from 1981 to 1984. Furthermore, the MICs at which 90% of the isolates were inhibited by five fluroquinolones, including OPC-17116, T-3761, DU-6859a, AM-1155, and Q-35, that have recently been synthesized but have not yet been introduced for clinical use in Japan for isolates from 1992 to 1993 were also 2- to 16-fold higher than those for isolates from 1981 to 1984. The gonococcal isolates from 1992 to 1993 showed no significant decreases in susceptibility to beta-lactams, tetracyclines, macrolides, and spectinomycin, compared with those for isolates from 1981 to 1984. Our data indicate that the incidence of gonococcal strains with decreased susceptibilities to fluoroquinolones is increasing in Japan.
Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis
Authors: Rouse D A , Li Z , Bai G H , Morris S L
Published: June 2012

Resistance to isoniazid in Mycobacterium tuberculosis has been associated with mutations in genes encoding the mycobacterial catalase-peroxidase (katG) and the InhA protein (inhA). Among the 26 isoniazid-resistant clinical isolates evaluated in this study, mutations in putative inhA regulatory sequences were identified in 2 catalase-positive isolates, katG gene alterations were detected in 20 strains, and 4 isolates had wild-type katG and inhA genes. Mutations in the katG gene were detected in all 11 catalase-negative isolates: one frameshift insertion, two partial gene deletions, and nine different missense mutations were identified. An arginine-to-leucine substitution at position 463 was detected in nine catalase-positive isolates. However, site-directed mutagenesis experiments demonstrated that the presence of a leucine at codon 463 did not alter the activity of the M. tuberculosis catalase-peroxidase and did not affect the capacity of this enzyme to restore isoniazid susceptibility to isoniazid-resistant, KatG-defective Mycobacterium smegmatis BH1 cells. These studies further support the association between katG and inhA gene mutations and isoniazid resistance in M. tuberculosis, while also suggesting that other undefined mechanisms of isoniazid resistance exist.
Incidence and mechanisms of resistance to the combination of amoxicillin and clavulanic acid in Escherichia coli
Authors: Stapleton P , Wu P J , King A , Shannon K , French G , Phillips I
Published: June 2012

Among Escherichia coli organisms isolated at St. Thomas's Hospital during the years 1990 to 1994, the frequency of resistance to amoxicillin-clavulanic acid (tested by disk diffusion in a ratio of 2:1) remained constant at about 5% of patient isolates (10 to 15% of the 41 to 45% that were amoxicillin resistant). Mechanisms of increased resistance were determined for 72 consecutively collected such amoxicillin-clavulanic acid-resistant isolates. MICs of the combination were 16-8 micrograms/ml for 51 (71%) of these and > or = 32-16 micrograms/ml for the remainder. The predominant mechanism was hyperproduction of enzymes isoelectrically cofocusing with TEM-1 (beta-lactamase activities, > 200 nmol of nitrocefin hydrolyzed per min per mg of protein) which was found in 44 isolates (61%); two isolates produced smaller amounts (approximately 150 nmol/min/mg) of such enzymes, and two isolates hyperproduced enzymes cofocusing with TEM-2. Eleven isolates produced enzymes cofocusing with OXA-1 beta-lactamase, which has previously been associated with resistance to amoxicillin-clavulanic acid. Ten isolates produced increased amounts of chromosomal beta-lactamase, and four of these additionally produced TEM-1 or TEM-2. Three isolates produced inhibitor-resistant TEM-group enzymes. In one of the enzymes (pI, 5.4), the amino acid sequence change was Met-67-->Val, and thus the enzyme is identical to TEM-34. Another (pI, 5.4) had the substitution Met-67-->Ile and is identical to IRT-I67, which we propose now be given the designation TEM-40. The third (pI, 5.2) had the substitution Arg-241-->Thr; this enzyme has not been reported previously and should be called TEM-41. The rarity and diversity of inhibitor-resistant TEM-group enzymes suggest that they are the result of spontaneous mutations that have not yet spread.
Different components in human serum inhibit multiplication of Cryptococcus neoformans and enhance fluconazole activity
Authors: Nassar F , Brummer E , Stevens D A
Published: June 2012

The inhibitory effect of human serum on the multiplication of Cryptococcus neoformans and the interaction with fluconazole were studied. Compared with cryptococcal multiplication in RPMI 1640 medium alone, 5% human serum in medium inhibited multiplication by 76% +/- 6% (n = 8). The inhibitory effect of human serum was donor independent, [corrected] heat stable (56 degrees C, 30 min), and not due to albumin or globulin. Bovine and murine sera were not inhibitory at that concentration. A fungistatic concentration of fluconazole (5.0 micrograms/ml) in medium plus 5% human serum resulted in 40% +/- 5% (n = 8) killing (reduction of inoculum CFU) in a 24-h assay. Bovine or murine sera did not have the enhancing effect, and this human serum activity was heat stable and donor independent. At 2.5 micrograms of fluconazole per ml, fungistasis by fluconazole plus human serum was significantly greater than with either alone. Higher serum concentrations [corrected] potentiated fluconazole more. At higher fluconazole concentrations (e.g., 20 micrograms/ml) fluconazole alone could kill, but serum potentiated this. A fluconazole-resistant isolate (MIC, 100 micrograms/ml) was not killed by fluconazole (5.0 micrograms/ml) in 5% human serum, but human serum potentiated the partial fluconazole inhibition. When human serum was dialyzed (molecular weight cutoff, 6,000 to 8,000) against phosphate-buffered saline, it lost the ability to synergize with fluconazole for killing Cryptococcus organisms but not the capacity to inhibit multiplication. Filtration of serum suggested the filtrate with a molecular weight of < 10,000 could interact synergistically with fluconazole for killing but could not inhibit cryptococcal multiplication. These findings indicate that human serum has two components, one (macromolecular) with a unique ability to inhibit C. neoformans and a low-molecular-weight component that enhances fluconazole anticryptococcal activity.
Prevention of experimental endotoxin shock by a monocyte activator
Authors: Passlick B , Labeta M O , Izbicki J R , Ostertag P , Löffler T , Siebeck M , Pichlmeier U , Schweiberer L , Ziegler-Heitbrock H W
Published: June 2012

In patients with polytrauma or major surgery, severe bacterial infections leading to septic shock and multiorgan failure are still a major cause of death. Prevention of septic shock in patients at risk would be an alternative to treatment of patients with overt septic shock. We therefore conducted a trial with the monocyte activator muramyl tripeptide phosphatidylethanolamine (MTP-PE) in an experimental pig model. Liposome encapsulated MTP-PE (50 micrograms/kg of body weight) or liposomes alone were given intravenously at 72 or 24 h before endotoxemia was induced by lipopolysaccharide (LPS), simultaneously with the induction of endotoxin shock, or 1 h thereafter. Pretreatment with MTP-PE at 72 and 24 h before endotoxemia was induced resulted in a reduction of endotoxin shock-induced mortality from 81.8% (9 of 11 animals) in the control group to 8.3% (1 of 12 animals) of the MTP-PE-pretreated animals (P < 0.001). The administration of MTP-PE 24 h before the induction of endotoxin shock was more effective (P < 0.01) than administration of MTP-PE 72 h before endotoxemia was induced (P = 0.05). The pretreated animals did not develop fever or cardiovascular complications, and pulmonary function was significantly improved. Furthermore, the alpha-form of the soluble CD14 LPS receptor in pig serum showed a marked decrease in LPS-treated animals, and this decrease was reduced by MTP-PE pretreatment at 24 h before endotoxemia was induced. When MTP-PE was given simultaneously with the induction of septic shock or 1 h thereafter, it did not influence either mortality or morbidity. In conclusion, pretreatment of pigs with MTP-PE improves several parameters of endotoxin shock and it reduces mortality. Patients with high risk of developing septic complications might benefit from a pretreatment with this monocyte-activating substance.
Prophylactic and therapeutic efficacies of poly(IC.LC) against respiratory influenza A virus infection in mice
Authors: Wong J P , Saravolac E G , Sabuda D , Levy H B , Kende M
Published: June 2012

Polyriboinosinic-polyribocytidylic acid [poly(IC.LC)] was evaluated for its prophylactic and therapeutic efficacies against respiratory influenza A virus infection in mice. Two doses of poly(IC.LC) (1 mg/kg of body weight per dose) administered intranasally within 12 days prior to infection with 10 50% lethal doses of mouse-adapted influenza A/PR/8 virus fully protected the mice against the infection. Determination of virus titers by hemagglutination and plaque assays showed more than a 2-log10 decrease in virus titers in lung homogenates of pretreated mice compared with those in the lungs of the nonpretreated group. Treatment of infected mice with poly(IC.LC) resulted in a modest (40%) survival rate. These results suggest that poly(IC.LC) provides a highly effective prophylaxis against respiratory influenza A virus infection in mice.
In vitro activities of ciprofloxacin, cefotaxime, ceftriaxone, chloramphenicol, and rifampin against fully susceptible and moderately penicillin-resistant Neisseria meningitidis
Authors: Blondeau J M , Yaschuk Y
Published: June 2012

Moderately penicillin-resistant Neisseria meningitidis was responsible for an outbreak of meningococcal disease in Saskatoon, Saskatchewan, Canada in 1993. We tested fully susceptible and moderately resistant strains of N. meningitidis against ciprofloxacin, cefotaxime, ceftriaxone, chloramphenicol, penicillin, and rifampin. Eighteen percent of the isolates were moderately resistant to penicillin (MIC > or = 0.06 microgram/ml) whereas susceptibility was 100% for the other agents tested.
First characterization of inhibitor-resistant TEM (IRT) beta-lactamases in Klebsiella pneumoniae strains
Authors: Lemozy J , Sirot D , Chanal C , Huc C , Labia R , Dabernat H , Sirot J
Published: June 2012

Two clinical strains of Klebsiella pneumoniae, TP 01 and TP 02, presented resistance to amoxicillin-clavulanate and were fully susceptible to cephalothin. These strains produced two beta-lactamases, SHV-1 and a TEM enzyme with a pI of 5.2. The previously described changes Arg-244-->Cys and Arg-244-->Ser in IRT-1 and IRT-2 (A. Belaaouaj, C. Lapoumeroulie, M. M. Caniça, G. Vedel, P. Nevot, R. Krishnamoorthy, and G. Paul, FEMS Microbiol. Lett. 120:75-80, 1994) were found in TEM enzymes from the TP 01 and TP 02 strains, respectively. This is the first report of inhibitor-resistant TEM (IRT) in species other than Escherichia coli from the family Enterobacteriaceae.
Activities of the semisynthetic glycopeptide LY191145 against vancomycin-resistant enterococci and other gram-positive bacteria
Authors: Nicas T I , Mullen D L , Flokowitsch J E , Preston D A , Snyder N J , Stratford R E , Cooper R D
Published: June 2012

LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin- and teicoplanin-resistant enterococci of < or = 4 micrograms/ml for 50% of isolates and < or = 16 micrograms/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 micrograms/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.
Demonstration of synergy with fluconazole and either ibuprofen, sodium salicylate, or propylparaben against Candida albicans in vitro
Authors: Scott E M , Tariq V N , McCrory R M
Published: June 2012

The combination of fluconazole with either ibuprofen, sodium salicylate, or propylparaben resulted in synergistic activity (fractional inhibitory index, < 0.5) against Candida albicans NCYC 620 in a microdilution checkerboard assay. Synergism between miconazole and ibuprofen was also demonstrated. In three or four clinical isolates of C. albicans from AIDS patients, the combination of fluconazole and ibuprofen was synergistic. Preparation of the inoculum and the growth conditions used were those recommended by the National Committee for Clinical Laboratory Standards for susceptibility testing. A visual estimation of total inhibition of growth and determination of an 80% reduction in the optical density at 492 nm compared with those for the control were taken as endpoints for the calculation of synergy, and a good correlation between both estimates was demonstrated.
Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans
Authors: Nakashima M , Uematsu T , Kosuge K , Kusajima H , Ooie T , Masuda Y , Ishida R , Uchida H
Published: June 2012

The pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, was examined in healthy male volunteers after the oral administration of a single dose of 100, 200, 400, or 600 mg and multiple doses of 300 mg twice daily for 6.5 days (13 total doses). Throughout the whole study period, AM-1155 was well tolerated in every subject. In the single-dose study, the concentrations in serum reached a peak between 1 and 2 h, and the peak concentrations were 0.873, 1.71, 3.35, and 5.41 micrograms/ml at the doses of 100, 200, 400, and 600 mg, respectively. The elimination half-life was 7 to 8 h, independently of the doses. The unchanged drug was excreted mainly in the urine, with 82 to 88% of the doses appearing for 72 h. The fecal recovery of the unchanged drug amounted to 5.7% for 72 h after a single oral administration of a 400-mg dose. Urinary excretion of metabolites was minimal. The serum protein binding was 20%, independently of the concentrations in serum. The concentrations in saliva were approximately 80% of those in serum. The intake of food had no effect on the pharmacokinetic parameters and urinary excretion of AM-1155 except the slight decrease in area under the concentration-time curve. The concurrent administration of probenecid prolonged the elimination half-life, increased the area under the concentration-time curve, and decreased the apparent total body clearance, renal clearance, urinary recovery of unchanged drug, and the excretion ratio (intrinsic renal clearance of AM-1155/creatinine clearance). This indicated that the tubular secretion contributed to the renal excretion of AM-1155. In the multiple-dose study, the concentrations of AM-1155 in serum and urine reached a steady state within 2 to 3 days. The measured concentrations in serum fitted well the simulation curve, which reflected the persistence of linear pharmacokinetics of AM-1155. In conclusion, AM-1155 is expected to be clinically useful because of its potent antibacterial activity and favorable pharmacokinetics.
Monitoring of co-trimoxazole concentrations in serum during treatment of pneumocystis carinii pneumonia
Authors: Joos B , Blaser J , Opravil M , Chave J P , Lüthy R
Published: June 2012

The purpose of this prospective randomized open trial was to investigate the impact of monitoring concentrations in serum on the efficacy and side effects of high-dose co-trimoxazole therapy. Forty consecutive patients with microscopically confirmed Pneumocystis carinii pneumonia were enrolled. Therapy was started with 5 and 25 mg of trimethoprim and sulfamethoxazole, respectively, per kg of body weight given every 6 h for 2 days and continued every 8 h either with (group A) or without (group B) monitoring and dose adjustments according to sulfamethoxazole levels in serum (target, 150 to 200 micrograms/ml) for a total of 21 days. Only 7 of 19 patients (83%). Patients who were treated for the full period and patients for whom co-trimoxazole was prematurely stopped had similar concentrations of sulfamethoxazole (157 +/- 52 versus 155 +/- 47 micrograms/ml) and trimethoprim (5.0 +/- 1.4 versus 5.6 +/- 1.0 microgram/ml). Concentrations of sulfamethoxazole and trimethoprim in group A (158 +/- 39 and 5.6 +/- 1.8 micrograms/ml, respectively) did not differ from those in group B (153 +/- 57 and 5.1 +/- 1.6 micrograms/ml, respectively), and the average daily maintenance doses for groups A (75.4 mg/kg plus 15.1 mg/kg) and B (76.4 mg/kg plus 15.3 mg/kg) were nearly identical. Although the average sulfamethoxazole concentrations were maintained within the target zone in the monitoring group (day 5, 160 +/- 44 micrograms/ml; day 10, 160 +/- 41 micrograms/ml; day 15, 168 +/- micrograms/ml; and day 21, 157 +/- 95 micrograms/ml), only 28% of the individual sulfamethoxazole levels were within the target range of 150 to 200 micrograms/ml after the dose adjustments (32% in group B without intervention). Response rates were similar in both groups. Complete response or improvement was observed in 18 of 19 (group A) and 19 of 21 (group B) patients. The method used for monitoring sulfamethoxazole levels with subsequent dose adjustment did not allow us to reliably achieve the target concentrations and did not significantly alter the incidence of side effects or the efficacy of the therapy.
Emergence of multiple-antibiotic-resistant Streptococcus pneumoniae in Hong Kong
Authors: Kam K M , Luey K Y , Fung S M , Yiu P P , Harden T J , Cheung M M
Published: June 2012

Two hundred four strains of Streptococcus pneumoniae isolated in Hong Kong from January 1993 to May 1995 were analyzed for their antibiotic susceptibilities and epidemiological patterns. The ages of the patients from whom the strains were isolated from 1 month to 93 years (median, 53 years); the male-to-female ratio was 2.8, with a predominance of males in the pediatric group. Fifty-nine (28.9%) strains showed reduced penicillin susceptibility, including 40 (19.6%) with frank penicillin resistance (MIC > 1 microgram/ml). Tetracycline resistance alone was found in 28.4% of strains. Isolates with reduced penicillin susceptibility were more common in children than adults (40 versus 23.9%, P = 0.02), and penicillin resistance rates were significantly higher in hospitalized patients than in outpatients (39.5 versus 12.5%; p < 0.001). Penicillin resistance was significantly associated with resistance to ceftriaxone, erythromycin, and tetracycline (P < 0.01) but not with ofloxacin or vancomycin (P = 0.5). Among eight different patterns of resistance to three or more antibiotics, the commonest one (14.2%) was multiple resistance to penicillin, chloramphenicol, ceftriaxone, erythromycin, and tetracycline. Emergence of multiple-antibiotic-resistant S. pneumoniae reflects changes in the pneumococcus itself and the general indiscriminate use of antibiotics in treatment of respiratory infections in Hong Kong.
Intraphagocytic growth induces an antibiotic-resistant phenotype of Legionella pneumophila
Authors: Barker J , Scaife H , Brown M R
Published: June 2012

The antimicrobial susceptibilities of Legionella pneumophila isolates grown either in U937 human monocytic cells or in Acanthamoeba polyphaga were studied after release from the host cells without further subculture. Time-survival studies showed that exposure of L. pneumophila cells, gown exclusively in vitro, to 5 micrograms of rifampin per ml resulted in at least 99% killing after 6 h and no detectable survivors at 24 h. Similar rates of killing were observed for in vitro-grown cells tested by exposure to ciprofloxacin. Conversely, time-survival studies revealed that macrophage-grown and amoeba-grown cells were ca. 1,000-fold more resistant to the activities of both drugs. Macrophage-grown cells treated with 5 micrograms of rifampin per ml showed 70 and 62% survival after 6 and 24 h, respectively. Intracellularly grown legionellae were also highly resistant to erythromycin (8 microgram/ml). After 24 h of exposure to the drug, there was 70 and 60% survival for amoeba-grown and macrophage-grown legionellae, respectively, whereas in vitro-grown cells showed a 2-log10 reduction in viable count. when intracellularly grown L. pneumophila cells were subcultured in broth for 48 h, they reverted to the phenotype characteristic of in vitro growth. Morphologically, the cells were larger than their intracellularly grown counterparts and resistance characteristics were lost. The susceptibilities of the subcultured cells to all three drugs were similar to those of Legionella cells grown exclusively in vitro. In view of these findings, the successful treatment of Legionnaires disease may be related as much to the resistance phenotype induced by intramacrophage growth as to the ability of the antibiotic to enter phagocytic cells.