bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Susceptibilities of Aerobic and Facultative Non-Spore-Forming Gram-Positive Bacilli to HMR 3647 (RU 66647) and 14 Other Antimicrobials
Authors: Soriano Francisco , Fernández-Roblas Ricardo , Calvo Raquel , García-Calvo Gloria 
Published: October 2018

ABSTRACT

The comparative in vitro activity of the ketolide HMR 3647 (RU 66647) and those of structurally related macrolide-lincosamide-streptogramin compounds (erythromycin, roxithromycin, azithromycin, clarithromycin, josamycin, lincomycin, pristinamycin, and quinupristin-dalfopristin) as well as those of benzylpenicillin, doxycycline, vancomycin, teicoplanin, levofloxacin, and rifapentine against 247 aerobic and facultative non-spore-forming gram-positive bacilli were determined by an agar dilution method. The ketolide was active against most organisms tested except
Corynebacterium striatum
, coryneform CDC group I2, and
Oerskovia
spp. The frequency of resistance to erythromycin and other macrolides as well as that to lincomycin was high. Pristinamycin and, to a lesser extent, quinupristin-dalfopristin were very active, but resistance to these agents was present in some strains of
Rhodococcus equi
,
Listeria
spp.,
C. striatum
,
Erysipelothrix rhusiopathiae
, and
Oerskovia
spp. HMR 3647 was very active against all erythromycin-sensitive and many erythromycin-nonsusceptible strains, especially
Corynebacterium minutissimum
,
Corynebacterium pseudodiphtheriticum
,
Corynebacterium amycolatum
, and
Corynebacterium jeikeium
. In vitro resistance to benzylpenicillin was common, but doxycycline, vancomycin, and teicoplanin were very active against most organisms tested except
E. rhusiopathiae
, against which glycopeptide antibiotics were not active. The in vitro activity of levofloxacin was remarkable, but resistance to this agent was common for
C. amycolatum
,
Corynebacterium urealyticum
,
C. jeikeium
, and
Oerskovia
spp. strains. Rifapentine was also very active in vitro against many organisms, but resistance to this agent was always present in
E. rhusiopathiae
and was very common in
C. striatum
and
C. urealyticum.
Metabolism in Human Cells of the
d
and
l
Enantiomers of the Carbocyclic Analog of 2′-Deoxyguanosine: Substrate Activity with Deoxycytidine Kinase, Mitochondrial Deoxyguanosine Kinase, and 5′-Nucleotidase
Authors: Bennett L. Lee , Allan Paula W. , Arnett Gussie , Shealy Y. Fulmer , Shewach Donna S. , Mason William S. , Fourel Isabelle , Parker William B. 
Published: October 2018

ABSTRACT

The carbocyclic analog of 2′-deoxyguanosine (CdG) has broad-spectrum antiviral activity. Because of recent observations with other nucleoside analogs that biological activity may be associated the
l
enantiomer rather than, as expected, with the
d
enantiomer, we have studied the metabolism of both enantiomers of CdG to identify the enzymes responsible for the phosphorylation of CdG in noninfected and virally infected human and duck cells. We have examined the enantiomers as substrates for each of the cellular enzymes known to catalyze phosphorylation of deoxyguanosine. Both enantiomers of CdG were substrates for deoxycytidine kinase (EC
2.7.1.74
) from MOLT-4 cells, 5′-nucleotidase (EC
3.1.3.5
) from HEp-2 cells, and mitochondrial deoxyguanosine kinase (EC
2.7.1.113
) from human platelets and CEM cells. For both deoxycytidine kinase and mitochondrial deoxyguanosine kinase, the
l
enantiomer was the better substrate. Even though the
d
enantiomer was the preferred substrate with 5′-nucleotidase, the rate of phosphorylation of the
l
enantiomer was substantial. The phosphorylation of
d
-CdG in MRC-5 cells was greatly stimulated by infection with human cytomegalovirus. The fact that the phosphorylation of
d
-CdG was stimulated by mycophenolic acid and was not affected by deoxycytidine suggested that 5′-nucleotidase was the enzyme primarily responsible for its metabolism in virally infected cells.
d
-CdG was extensively phosphorylated in duck hepatocytes, and its phosphorylation was not affected by infection with duck hepatitis B virus. These results are of importance in understanding the mode of action of
d
-CdG and related analogs and in the design of new biologically active analogs.
Drug Evaluation of Concurrent
Pneumocystis carinii
,
Toxoplasma gondii
, and
Mycobacterium avium
Complex Infections in a Rat Model
Authors: Brun-Pascaud Monique , Rajagopalan-Levasseur Premavathy , Chau Françoise , Bertrand Guylène , Garry Louis , Derouin Francis , Girard Pierre-Marie 
Published: October 2018

ABSTRACT

We present a new experimental model for the simultaneous evaluation of the activities of drugs against
Pneumocystis carinii
,
Toxoplasma gondii
, and
Mycobacterium avium
complex infections. Rats latently infected with
P. carinii
were challenged with the MO-1 strain of
M. avium
and then immunosuppressed with corticosteroids for 7 weeks. At week 5 the RH strain of
T. gondii
was intraperitoneally injected. Organs were examined for the three pathogens after death or killing of the animals at week 7. Without treatment, rats challenged with
T. gondii
died with pulmonary
P. carinii
infection and disseminated
T. gondii
and
M. avium
infections. In order to assess the value of the model for evaluation of the activities of drugs, we administered by oral gavage for 7 weeks drugs or combinations of drugs selected for their individual efficacies against at least one pathogen. We found that clarithromycin with sulfamethoxazole, clarithromycin with atovaquone, roxithromycin with sulfamethoxazole or dapsone, and rifabutin with atovaquone were effective against the three infections, whereas PS-15 with dapsone and trimethoprim with sulfamethoxazole were active against
Toxoplasma
and
Pneumocystis
infections only. This triple-infection rat model offers a new tool for the simultaneous evaluation of the activities of drugs against three of the major opportunistic infections occurring in immunosuppressed individuals.
Disposition of the Acyclic Nucleoside Phosphonate (
S
)-9(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine
Authors: Bijsterbosch Martin K. , Smeijsters Louis J. J. W. , van Berkel Theo J. C. 
Published: October 2018

ABSTRACT

The acyclic nucleoside phosphonate (
S
)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(
S
)-HPMPA] has been shown to be active against pathogens, like hepatitis B viruses and
Plasmodium
parasites, that infect parenchymal liver cells. (
S
)-HPMPA is therefore an interesting candidate drug for the treatment of these infections. To establish effective therapeutic protocols for (
S
)-HPMPA, it is essential that the kinetics of its hepatic uptake be evaluated and that the role of the various liver cell types be examined. In the present study, we investigated the disposition of (
S
)-HPMPA and assessed its hepatic uptake. Rats were intravenously injected with [
3
H](
S
)-HPMPA, and after an initial rapid distribution phase (360 ± 53 ml/kg of body weight), the radioactivity was cleared from the circulation with a half-life of 11.7 ± 1.4 min. The tissue distribution of [
3
H](
S
)-HPMPA was determined at 90 min after injection (when >99% of the dose cleared). Most (57.0% ± 1.1%) of the injected [
3
H](
S
)-HPMPA was excreted unchanged in the urine. The radioactivity that was retained in the body was almost completely recovered in the kidneys and the liver (68.4% ± 2.5% and 16.1% ± 0.4% of the radioactivity in the body, respectively). The uptake of [
3
H](
S
)-HPMPA by the liver occurred mainly by parenchymal cells (92.1% ± 3.4% of total uptake by the liver). Kupffer cells and endothelial cells accounted for only 6.1% ± 3.5% and 1.8% ± 0.8% of the total uptake by the liver, respectively. Preinjection with probenecid reduced the hepatic and renal uptake of [
3
H](
S
)-HPMPA by approximately 75%, which points to a major role of a probenecid-sensitive transporter in the uptake of (
S
)-HPMPA by both tissues. In conclusion, we show that inside the liver, (
S
)-HPMPA is mainly taken up by parenchymal liver cells. However, the level of uptake by the kidneys is much higher, which leads to nephrotoxicity. An approach in which (
S
)-HPMPA is coupled to carriers that are specifically taken up by parenchymal cells may increase the effectiveness of the drug in the liver and reduce its renal toxicity.
Defluorinated Sparfloxacin as a New Photoproduct Identified by Liquid Chromatography Coupled with UV Detection and Tandem Mass Spectrometry
Authors: Engler Michael , Rüsing Guido , Sörgel Fritz , Holzgrabe Ulrike 
Published: October 2018

ABSTRACT
Photodegradation of sparfloxacin was observed by means of high-pressure liquid chromatography with UV detection and liquid chromatography coupled with UV detection and tandem mass spectrometry (LC-MS/MS). Three products were detected. Comparison with an independently synthesized derivative of sparfloxacin revealed the structure of one product which is believed to be 8-desfluorosparfloxacin. The second product is likely to be formed by the splitting off of a fluorine and a cyclopropyl ring. Thus, photodefluorination of quinolone antibacterial agents is found and proved for the first time by LC-MS/MS.
Cloning and Sequencing of the Gene Encoding Toho-2, a Class A β-Lactamase Preferentially Inhibited by Tazobactam
Authors: Ma Ling , Ishii Yoshikazu , Ishiguro Masaji , Matsuzawa Hiroshi , Yamaguchi Keizo 
Published: October 2018

ABSTRACT

Escherichia coli
TUM1083, which is resistant to ampicillin, carbenicillin, cephaloridine, cephalothin, piperacillin, cefuzonam, and aztreonam while being sensitive to cefoxitin, moxalactam, cefmetazole, ceftazidime, and imipenem, was isolated from the urine of a patient treated with β-lactam antibiotics. The β-lactamase (Toho-2) purified from the bacteria hydrolyzed β-lactam antibiotics such as penicillin G, carbenicillin, cephaloridine, cefoxitin, cefotaxime, ceftazidime, and aztreonam and especially had increased relative hydrolysis rates for cephalothin, cephaloridine, cefotaxime, and ceftizoxime. Different from other extended-spectrum β-lactamases, Toho-2 was inhibited 16-fold better by the β-lactamase inhibitor tazobactam than by clavulanic acid. Resistance to β-lactams was transferred by conjugation from
E. coli
TUM1083 to
E. coli
ML4909, and the transferred plasmid was about 54.4 kbp, belonging to the incompatibility group IncFII. The cefotaxime resistance gene for Toho-2 was subcloned from the 54.4-kbp plasmid. The sequence of the gene was determined, and the open reading frame of the gene was found to consist of 981 bases. The nucleotide sequence of the gene (DDBJ accession no.
D89862
) designated as
bla
toho
was found to have 76.3% identity to class A β-lactamase CTX-M-2 and 76.2% identity to Toho-1. It has 55.9% identity to SHV-1 β-lactamase and 47.5% identity to TEM-1 β-lactamase. Therefore, the newly isolated β-lactamase designated as Toho-2 produced by
E. coli
TUM1083 is categorized as an enzyme similar to Toho-1 group β-lactamases rather than to mutants of TEM or SHV enzymes. According to the amino acid sequence deduced from the DNA sequence, the precursor consisted of 327 amino acid residues. Comparison of Toho-2 with other β-lactamase (non-Toho-1 group) suggests that the substitutions of threonine for Arg-244 and arginine for Asn-276 are important for the extension of the substrate specificity.
Postantibiotic Effect and Postantibiotic Sub-MIC Effect of Levofloxacin Compared to Those of Ofloxacin, Ciprofloxacin, Erythromycin, Azithromycin, and Clarithromycin against 20 Pneumococci
Authors: Spangler Sheila K. , Lin Gengrong , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT
The postantibiotic effect (PAE) (10 times the MIC of quinolones, 5 times the MIC of macrolides) and postantibiotic sub-MIC effect (PAE-SME) at 0.125, 0.25, and 0.5 times the MIC were determined for levofloxacin, ciprofloxacin, ofloxacin, erythromycin, azithromycin, and clarithromycin against 20 pneumococci. Quinolone PAEs ranged between 0.5 and 6.5 h, and macrolide PAEs ranged between 1 and 6 h. Measurable PAE-SMEs (in hours) at the three concentrations were 1 to 5, 1 to 8, and 1 to 8, respectively, for quinolones and 1 to 8, 1 to 8, and 1 to 6, respectively, for macrolides.
Antipneumococcal Activity of Grepafloxacin Compared to That of Other Agents by Time-Kill Methodology
Authors: Pankuch Glenn A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT
Time-kill studies compared the activities of grepafloxacin with those of ciprofloxacin, levofloxacin, sparfloxacin, amoxicillin-clavulanate, and clarithromycin against 12 pneumococcal strains. Grepafloxacin was bactericidal after 24 h against all strains at a concentration of ≤0.5 μg/ml, while sparfloxacin, levofloxacin, and ciprofloxacin were bactericidal at concentrations of ≤1.0, ≤2.0, and ≤8.0 μg/ml, respectively. Amoxicillin-clavulanate and clarithromycin were bactericidal at 2× the MIC after 24 h against 12 of 12 strains and against all 8 macrolide-susceptible strains, respectively.
In Vitro Activities of Clinafloxacin against Contemporary Clinical Bacterial Isolates from 10 North American Centers
Authors: Fuchs Peter C. , Barry Arthur L. , Brown Steven D. 
Published: October 2018

ABSTRACT
Clinafloxacin was more active than ciprofloxacin against 4,213 aerobic and facultative anaerobic bacterial isolates from 10 medical centers, as tested by broth microdilution and disk diffusion methods. The percentage of 201 anaerobes susceptible to clinafloxacin by broth microdilution was comparable to cefoxitin. Our data support the proposed disk diffusion interpretive criteria for aerobic bacteria with 5-μg clinafloxacin disks.
Prophylaxis of
Plasmodium falciparum
Infection in a Human Challenge Model with WR 238605, a New 8-Aminoquinoline Antimalarial
Authors: Brueckner Ralf P. , Coster Trinka , Wesche David L. , Shmuklarsky Moshe , Schuster Brian G. 
Published: October 2018

ABSTRACT

The prophylactic efficacy of WR 238605, a primaquine analog, was studied with a human
Plasmodium falciparum
challenge model. A single oral dose of 600 mg, administered 1 day prior to challenge, successfully protected three of four subjects. The fourth subject developed mild, oligosymptomatic malaria on day 31, with drug concentrations one-half of those in the protected individuals. WR 238605 appears to be a promising prophylactic drug for
P. falciparum
malaria.
Phase I Safety and Pharmacokinetics Study of Micronized Atovaquone in Human Immunodeficiency Virus-Infected Infants and Children
Authors: Hughes Walter , Dorenbaum Alejandro , Yogev Ram , Beauchamp Belinda , Xu Jing , McNamara James , Moye John , Purdue Lynette , van Dyke Russell , Rogers Michael , Sadler Brian , Group The Pediatric Aids Clinical Trials 
Published: October 2018

ABSTRACT

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 μg/ml is associated with therapeutic success in more than 95% of patients with
Pneumocystis carinii
pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 μg/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of
P. carinii
pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.
Minocycline and Cefotaxime in the Treatment of Experimental Murine
Vibrio vulnificus
Infection
Authors: Chuang Yin-Ching , Ko Wen-Chien , Wang Shan-Tair , Liu Jien-Wei , Kuo Chih-Feng , Wu Jiunn-Jong , Huang Kun-Yen 
Published: October 2018

ABSTRACT

We conducted an in vivo study with the mouse model of
Vibrio vulnificus
infection to evaluate the efficacies of therapy with minocycline or cefotaxime alone and in combination.
V. vulnificus
was introduced subcutaneously into the area over the right thigh. The inoculum size ranged from 1.0 × 10
3
to 1.2 × 10
8
CFU from experiment to experiment but was constant for all animals in the same experiment. Antibiotics were given intraperitoneally 2 h after the bacteria were inoculated. In experiments 1 to 4, the standard dose for humans was used to treat the infection, while in experiment 5, five times the standard dose for humans was used to treat the infection. In experiment 1, with a small inoculum of 5 × 10
3
CFU, all mice in the saline-treated control group and the cefotaxime-, minocycline-, and combined antibiotic-treated groups survived. In experiment 2, with a moderate inoculum of 1.2 × 10
5
CFU, all the mice in the three antibiotic-treated groups survived, while only two of nine mice in the control group survived. In experiment 3, with a large inoculum of 8.0 × 10
7
CFU, six of nine mice in the combined antibiotic-treated group survived, while only one of nine mice in the cefotaxime-treated group and none of the mice in the control and minocycline-treated groups survived. In experiment 4, with a large inoculum of 1.2 × 10
8
CFU, 8 of 20 mice in the combined antibiotic-treated group survived, while none of the 20 mice in the control group, the group treated with cefotaxime alone, and the group treated with minocycline alone survived. In experiment 5, in which mice were infected with a large inoculum of 6.6 × 10
7
CFU and treated with five times the standard human dose of antibiotics, 10 of 12 mice in the combined antibiotic-treated group survived, while only 4 of 12 mice in the minocycline-treated group, 1 of 12 mice in the cefotaxime-treated group, and none of the mice in the control group survived. In experiments 3 to 5, the difference in the survival rates between the combined antibiotic-treated and minocycline-treated groups was statistically significant (
P
< 0.05). These results indicate that combination therapy with cefotaxime and minocycline is distinctly more advantageous than therapy with the single antibiotic regimen for the treatment of severe experimental
V. vulnificus
infections.
Phenotypic Study of Resistance of β-Lactamase-Inhibitor-Resistant TEM Enzymes Which Differ by Naturally Occurring Variations and by Site-Directed Substitution at Asp
276
Authors: Caniça M. Manuela , Caroff Nathalie , Barthélémy Michel , Labia Roger , Krishnamoorthy Rajagopal , Paul Gérard , Dupret Jean-Marie 
Published: October 2018

ABSTRACT

At this time an amino acid substitution at position 276 in the TEM-1 enzyme is associated with an additional substitution at position 69 in natural β-lactamase-inhibitor-resistant (IRT) β-lactamases. The effect of the Asn
276
→Asp substitution on resistance was assessed with the Asn276Asp variant, generated by site-directed mutagenesis. The mutant was resistant to β-lactamase inhibitors, but the MICs of amoxicillin combined with clavulanic acid or tazobactam were strikingly different for
E. coli
strains producing the Asn276Asp variant and those producing naturally occurring IRTs with single or double substitutions. The inhibitory effects of clavulanic acid and tazobactam were the same in IRTs with substitutions at position 69 (IRT-5 and IRT-6). The effect of clavulanic acid on the MICs of amoxicillin for the Asn276Asp variant was greater than that of tazobactam. In IRTs with double substitutions, at positions 69 plus 276 (IRT-4, IRT-7, and IRT-8) or 69 plus 275 (IRT-14), tazobactam was a more potent inhibitor than clavulanic acid. The effect of the Asn
276
→Asp substitution on the values of the kinetic constants and the concentration required to inhibit by 50% the hydrolysis of benzylpenicillin confirms that this single mutation is responsible for resistance to β-lactamase inhibitors. Molecular modeling of the Asn276Asp mutant shows that Asp
276
can form two salt bonds with Arg
244
close to the penicillin-binding cavity. The addition of the Asp
276
mutation to that preexisting at position 69 confers a higher selective advantage to bacteria, as shown by the reduction in β-lactamase inhibitor efficiencies of the double variants. Therefore, the emergence of multiple mutations in TEM β-lactamases by virtue of the use of β-lactamase inhibitors increases selection pressure resulting in the convergent evolution of resistant strains.
Effect of Metronidazole Resistance on Bacterial Eradication of
Helicobacter pylori
in Infected Children
Authors: Raymond J. , Kalach N. , Bergeret M. , Benhamou P. H. , Barbet J. P. , Gendrel D. , Dupont C. 
Published: October 2018

ABSTRACT

A prospective study was performed with 23
Helicobacter pylori
-infected children (mean age, 9.5 ± 4.4 years) with clinical symptoms of gastritis and positive results of culture and histologic examination of gastric biopsy specimens to evaluate the influence of antibiotic resistance on eradication. Positive children were treated for 4 weeks with lansoprazole and for 2 weeks with either amoxicillin-metronidazole or spiramycin (a macrolide)-metronidazole. At endoscopy 1 month after the discontinuation of therapy, the eradication rate and improvement of histologically related gastritis were significantly dependent on the susceptibility or the resistance of the infecting organism to metronidazole (83 versus 17% and 88 versus 16.6%, respectively). Pretreatment determination of the susceptibility is appropriate in any anti-
H. pylori
regimen, including one with metronidazole.
β-Lactamases Responsible for Resistance to Expanded-Spectrum Cephalosporins in
Klebsiella pneumoniae
,
Escherichia coli
, and
Proteus mirabilis
Isolates Recovered in South Africa
Authors: Pitout J. D. D. , Thomson K. S. , Hanson N. D. , Ehrhardt A. F. , Moland E. S. , Sanders C. C. 
Published: October 2018

ABSTRACT

Although resistance to the expanded-spectrum cephalosporins among members of the family
Enterobacteriaceae
lacking inducible β-lactamases occurs virtually worldwide, little is known about this problem among isolates recovered in South Africa. Isolates of
Klebsiella pneumoniae
,
Escherichia coli
, and
Proteus mirabilis
resistant to expanded-spectrum cephalosporins recovered from patients in various parts of South Africa over a 3-month period were investigated for extended-spectrum β-lactamase production. Antibiotic susceptibility was determined by standard disk diffusion and agar dilution procedures. Production of extended-spectrum β-lactamases was evaluated by using the double-disk test, and the β-lactamases were characterized by spectrophotometric hydrolysis assays and an isoelectric focusing overlay technique which simultaneously determined isoelectric points and general substrate or inhibitor characteristics. DNA amplification and sequencing were performed to confirm the identities of these enzymes. The
P. mirabilis
and
E. coli
isolates were found to produce TEM-26-type, SHV-2, and SHV-5 extended-spectrum β-lactamases. An AmpC-related enzyme which had a pI of 8.0 and which conferred resistance to cefoxitin as well as the expanded-spectrum cephalosporins was found in a strain of
K. pneumoniae
. This is the first study which has identified organisms producing different extended-spectrum β-lactamases from South Africa and the first report describing strains of
P. mirabilis
producing a TEM-26-type enzyme. The variety of extended-spectrum β-lactamases found among members of the family
Enterobacteriaceae
isolated from major medical centers in South Africa is troubling and adds to the growing list of countries where these enzymes pose a serious problem for antimicrobial therapy.