bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antipneumococcal Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Erythromycin, Azithromycin, Clarithromycin, Clindamycin, and Telithromycin
Authors: Matic Vlatka , Kosowska Klaudia , Bozdogan Bulent , Kelly Linda M. , Smith Kathy , Ednie Lois M. , Lin Gengrong , Credito Kim L. , Clark Catherine L. , McGhee Pamela , Pankuch Glenn A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2004

ABSTRACT

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with
erm
(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were ≥0.5 μg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No
mef
(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two
mef
(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 μg/ml. Single-step studies showed mutation frequencies <5.0 × 10
−10
to 3.5 × 10
−7
for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 × 10
−7
to >4.3 × 10
−3
for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.
Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against
Haemophilus influenzae
Authors: Kosowska Klaudia , Credito Kim , Pankuch Glenn A. , Hoellman Dianne , Lin Gengrong , Clark Catherine , Dewasse Bonifacio , McGhee Pamela , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2004

ABSTRACT

The MIC at which 50% of strains are inhibited (MIC
50
) and the MIC
90
of GW 773546, a novel macrolide, were 1.0 and 2.0 μg/ml, respectively, for 223 β-lactamase-positive, β-lactamase-negative, and β-lactamase-negative ampicillin-resistant
Haemophilus influenzae
strains. The MIC
50
s and MIC
90
s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 μg/ml, respectively, while the MIC
50
and MIC
90
of azithromycin were 1.0 and 2.0 μg/ml, respectively. The MIC
50
and MIC
90
of erythromycin were 4.0 and 8.0 μg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 μg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 × 10
−9
to 2.2 × 10
−6
with GW 773546, 1.5 × 10
−9
to 6.0 × 10
−4
with GW 708408, and 7.1 × 10
−9
to 3.8 × 10
−4
with telithromycin, whereas the frequencies were 1.3 × 10
−9
to 6.0 × 10
−4
with erythromycin and azithromycin and 2.0 × 10
−9
to 2.0 × 10
−3
with clarithromycin. Alterations in the L22 protein (which were predominant) and the L4 protein were present in mutants selected by the single-step selection process. The postantibiotic effects of GW 773546, GW 708408, and telithromycin for seven
H. influenzae
strains were 6.6 h (range, 5.2 to 8.8 h), 4.7 h (range, 2.6 to 6.9 h), and 6.4 h (range, 3.8 to 9.7 h), respectively. The results of in vitro studies obtained with both novel macrolides were similar to those obtained with telithromycin and better than those obtained with older macrolides.
Chemical Diversity of Polyene Macrolides Produced by
Streptomyces noursei
ATCC 11455 and Recombinant Strain ERD44 with Genetically Altered Polyketide Synthase NysC
Authors: Bruheim Per , Borgos Sven E.F. , Tsan Pascale , Sletta Håvard , Ellingsen Trond E. , Lancelin Jean-Marc , Zotchev Sergey B. 
Published: October 2004

ABSTRACT

The gram-positive bacterium
Streptomyces noursei
ATCC 11455 produces a complex mixture of polyene macrolides generally termed nystatins. Although the structures for nystatins A
1
and A
3
have been reported, the identities of other components of the nystatin complex remain obscure. Analyses of the culture extract from the
S. noursei
wild type revealed the presence of several nystatin-related compounds for which chemical structures could be suggested on the basis of their molecular weights, their UV spectra, and knowledge of the nystatin biosynthetic pathway. Nuclear magnetic resonance (NMR) studies with one of these polyene macrolides identified it as a nystatin analogue containing a mycarose moiety at C-35. A similar investigation was performed with the culture extract of the ERD44 mutant, which has a genetically altered polyketide synthase (PKS) NysC and which was previously shown to produce a heptaene nystatin analogue. The latter compound, tentatively named S44HP, and its derivative, which contains two deoxysugar moieties, were purified; and their structures were confirmed by NMR analysis. Nystatin analogues with an expanded macrolactone ring were also observed in the extract of the ERD44 mutant, suggesting that the altered PKS can “stutter” during the polyketide chain assembly. These data provide new insights into the biosynthesis of polyene macrolide antibiotics and the functionalities of PKSs and post-PKS modification enzymes.
OXA-60, a Chromosomal, Inducible, and Imipenem-Hydrolyzing Class D β-Lactamase fromRalstonia pickettii
Authors: Girlich Delphine , Naas Thierry , Nordmann Patrice 
Published: October 2004

ABSTRACTA chromosomally encoded oxacillinase, OXA-22, had been characterized fromRalstonia pickettiiPIC-1 that did not explain by itself the resistance profile of this strain to β-lactams. Thus, further analysis of the genetic background of this species led to the identification of another oxacillinase, OXA-60, that was expressed only after β-lactam induction. This chromosomally encoded oxacillinase shared 19% amino acid identity with OXA-22. It has a narrow-spectrum hydrolysis profile that includes imipenem. OXA-60-like enzymes were identified in severalR. pickettiistrains. Gene inactivation and induction studies of theblaOXA-60andblaOXA-22genes inR. pickettiiidentified the relative contribution of each oxacillinase to the resistance profile ofR. pickettiito β-lactams.
Hypermutation and the Preexistence of Antibiotic-Resistant
Pseudomonas aeruginosa
Mutants: Implications for Susceptibility Testing and Treatment of Chronic Infections
Authors: Oliver Antonio , Levin Bruce R. , Juan Carlos , Baquero Fernando , Blázquez Jesús 
Published: October 2004

ABSTRACT

Whether or not resistant mutants will be present before the start of antibiotic treatment of an initially susceptible population of bacteria depends on the size of the infecting population, the rate of mutation to resistance, and the amount of time that the population has been maintained. In the present investigation, we argue that for the treatment of chronic infections caused by hypermutable
Pseudomonas aeruginosa
of the sort frequently found in cystic fibrosis patients, mutants resistant to all single antipseudomonal drugs will almost invariably be present in a high proportion at the onset of treatment, and consequently, these strains should be considered resistant to all agents when they are used as monotherapy. Using a construct of
P. aeruginosa
strain PAO1 with a
mutS
deletion (strain PAOΔ
mutS
), we show that when in vitro populations of less than 5 × 10
4
seemingly susceptible hypermutable bacteria are confronted with any of 11 antipseudomonal agents, mutants for which the MICs and the minimum bactericidal concentrations are in the range of clinical resistance will almost invariably ascend to dominance within 24 to 36 h. This does not occur for PAO1 without the
mutS
deletion. The results of our detailed analysis of this evolution of acquired resistance to two of these antibiotics, imipenem and ciprofloxacin, indicate that although the rates of mutation to resistance in PAOΔ
mutS
are on the order of 1 × 10
−6
per generation, resistant mutants are very likely to either be present in cultures of between 2 × 10
4
and 4 × 10
4
bacteria or arise after the bacterial populations are confronted with antibiotics. We also demonstrate with in vitro experiments that the problem of acquired resistance to treatment with single antibiotics can be thwarted by combination therapy with pairs of antibiotics of different classes with synergistic activities. We discuss the clinical implications of our analysis of these observations.
Evolution of the Antimicrobial Resistance ofStaphylococcusspp. in Spain: Five Nationwide Prevalence Studies, 1986 to 2002
Authors: Cuevas Oscar , Cercenado Emilia , Vindel Ana , Guinea Jesús , Sánchez-Conde Matilde , Sánchez-Somolinos Mar , Bouza Emilio 
Published: October 2004

ABSTRACTData regarding the evolution ofStaphylococcusresistance in a whole country have a definite influence on the design of empirical treatment regimens. Nevertheless, incidence studies over long periods of time are expensive and very difficult to carry out. In order to ascertain the present situation of the antimicrobial resistance ofStaphylococcusin Spain and the change of this resistance over time, we performed five point prevalence studies (1986 to 2002) in a large group of Spanish hospitals (from 68 institutions in 1986 to 143 in 2002) collecting allStaphylococcusstrains isolated on a single selected day. All microorganisms were identified in the five studies at the same laboratory, and antimicrobial susceptibility testing was performed against 17 antimicrobial agents by the agar dilution method and a microdilution method. During this period, there was an overall increase in resistance to most antimicrobials amongStaphylococcus aureus/coagulase-negative staphylococci, mainly to oxacillin (1.5%/32.5% in 1986 versus 31.2%/61.3% in 2002) (P< 0.001), erythromycin (7%/41.1% in 1986 versus 31.7%/63% in 2002) (P< 0.001), gentamicin (5.2%/25.4% in 1986 versus 16.9%/27.8% in 2002) (P< 0.001;P= 0.5), and ciprofloxacin (0.6%/1.1% in 1986 versus 33.9%/44.9% in 2002) (P< 0.001). All of the isolates were uniformly susceptible to glycopeptides, linezolid, and quinupristin/dalfopristin. Resistance ofS. aureusto trimethoprim/sulfamethoxazole was very low (from 0.5% to 2.1%) (P= 0.152). Periodic performance of prevalence studies is a useful, inexpensive, and easy tool to know the nationwide situation of a microorganism and its resistance to antimicrobials; it also helps us assess the emergence and spread of antimicrobial resistance.
Infections with NontyphoidalSalmonellaSpecies Producing TEM-63 or a Novel TEM Enzyme, TEM-131, in South Africa
Authors: Kruger Tersia , Szabo Dora , Keddy Karen H. , Deeley Kathleen , Marsh Jane W. , Hujer Andrea M. , Bonomo Robert A. , Paterson David L. 
Published: October 2004

ABSTRACTSalmonellaspp. producing extended-spectrum beta-lactamases (ESBLs) have been reported in many countries, but there is no information on their prevalence in Africa. ESBL-producingSalmonella entericaserotype Isangi andS. entericaserotype Typhimurium strains have been noted in South Africa since 2001. A total of 160 consecutive isolates ofSalmonellaspp. were collected from 13 hospitals located in different cities in South Africa over a 5-month period from December 2002 to April 2003. All strains were screened for production of ESBLs by the double disk diffusion test and for AmpC production by assessing resistance to cefoxitin.blaSHV,blaTEM,blaCTX-M, andblaCMY-2were sought from all ESBL-positive and cefoxitin-resistant isolates. A total of 15.6% (25 of 160) isolates produced SHV or TEM ESBLs, and 1.9% (3 of 160) produced CMY-2. NineS. entericaserotype Typhimurium, eightS. entericaserotype Isangi, and threeS. entericaserotype Muenchen strains produced either TEM-63 or a derivative of TEM-63 designated TEM-131. Both TEM-63 and TEM-131 have an isoelectric point of 5.6, and their sequences have the following amino acid substitutions compared to the TEM-1 sequence: Leu21Phe, Glu104Lys, Arg164Ser, and Met182Thr. Additionally, TEM-131 has an Ala237Thr substitution. ESBL-producingSalmonellaspp. have become a significant public health problem in South Africa with particular implications for the treatment of serious nontyphoidalSalmonellainfections in children, for whom extended-spectrum cephalosporins were the preferred treatment.
Molecular Mechanisms of Primary Resistance to Flucytosine in
Candida albicans
Authors: Hope William W. , Tabernero Lydia , Denning David W. , Anderson Michael J. 
Published: October 2004

ABSTRACT

Primary resistance in
Candida albicans
to flucytosine (5-FC) was investigated in 25 strains by identifying and sequencing the genes
FCA1
,
FUR1
,
FCY21
, and
FCY22
, which code for cytosine deaminase, uracil phosphoribosyltransferase (UPRT), and two purine-cytosine permeases, respectively. These proteins are involved in pyrimidine salvage and 5-FC metabolism. An association between a polymorphic nucleotide and resistance to 5-FC was found within
FUR1
where the substitution of cytidylate for thymidylate at nucleotide position 301 results in the replacement of arginine with cysteine at amino acid position 101 in UPRT. Isolates that are homozygous for this mutation display increased levels of resistance to 5-FC, whereas heterozygous isolates have reduced susceptibility. Three-dimensional protein modeling of UPRT suggests that the Arg101Cys mutation disturbs the quaternary structure of the enzyme, which is postulated to compromise optimal enzyme activity. A single resistant isolate, lacking the above polymorphism in
FUR1
, has a homozygous polymorphism in
FCA1
that results in a glycine-to-aspartate substitution at position 28 in cytosine deaminase.
In Vitro Evolution of Itraconazole Resistance in
Aspergillus fumigatus
Involves Multiple Mechanisms of Resistance
Authors: da Silva Ferreira Márcia Eliana , Capellaro José Luiz , dos Reis Marques Everaldo , Malavazi Iran , Perlin David , Park Steven , Anderson James B. , Colombo Arnaldo L. , Arthington-Skaggs Beth A. , Goldman Maria Helena S. , Goldman Gustavo H. 
Published: October 2004

ABSTRACT

We investigated the evolution of resistance to the antifungal drug itraconazole in replicate populations of
Aspergillus fumigatus
that were founded from a strain with a genotype of sensitivity to a single drug and then propagated under uniform conditions. For each population, conidia were serially transferred 10 times to agar medium either with or without itraconazole. After 10 transfers in medium supplemented with itraconazole, 10 itraconazole-resistant mutant strains were isolated from two populations. These mutant strains had different growth rates and different levels of itraconazole resistance. Analysis of the ergosterol contents of these mutants showed that they accumulate ergosterol when they are grown in the presence of itraconazole. The replacement of the
CYP51A
gene of the wild-type strain changed the susceptibility pattern of this strain to one of itraconazole resistance only when
CYP51A
genes with N22D and M220I mutations were used as selectable marker genes. Real-time quantitative reverse transcription-PCR was used to assess the levels of expression of the
Afumdr1
,
Afumdr2
,
Afumdr3
,
Afumdr4
,
AtrF
transporter,
CYP51A
, and
CYP51B
genes in these mutant strains. Most mutants showed either constitutive high-level expression or induction upon exposure of
Afumdr3
,
Afumdr4
, and
AtrF
to itraconazole. Our results suggest that overexpression of drug efflux pumps and/or selection of drug target site mutations are at least partially responsible for itraconazole resistance and could be considered mechanisms for the emergence of clinical resistance to this drug.
Evidence for Biliary Excretion of Vancomycin into Stool during Intravenous Therapy: Potential Implications for Rectal Colonization with Vancomycin-Resistant Enterococci
Authors: Currie Brian P. , Lemos-Filho Luciano 
Published: October 2004

ABSTRACT
Sixty-three stool samples and five bile samples were prospectively collected from 33 patients receiving intravenous vancomycin therapy and were quantitatively analyzed for vancomycin by a competitive immunoassay. Vancomycin was excreted via bile into the stools of almost all patients at concentrations of 3.3 to 94.8 μg/ml after ≥5 days of a therapy of 1 g every 12 h.
Novel Mutations within the
embB
Gene in Ethambutol-Susceptible Clinical Isolates of
Mycobacterium tuberculosis
Authors: Lee Ann S. G. , Othman Siti Noor Khadijah , Ho Yu Min , Wong Sin Yew 
Published: October 2004

ABSTRACT

Genetic analysis of the
embB
gene revealed mutations in 17 (68%) of 25 ethambutol (EMB) resistant isolates (M306I, M306V, M306L, Q497R) but also in 4 (20%) of 20 EMB-susceptible isolates of
Mycobacterium tuberculosis
, namely, an ATG→ATM substitution resulting in M306I, G406N, and the novel alterations M423I and A659T.
Antimicrobial Susceptibility Patterns among Viridans Group Streptococcal Isolates from Infective Endocarditis Patients from 1971 to 1986 and 1994 to 2002
Authors: Prabhu Rajesh M. , Piper Kerryl E. , Baddour Larry M. , Steckelberg James M. , Wilson Walter R. , Patel Robin 
Published: October 2004

ABSTRACT
To determine whether changes in antimicrobial resistance have occurred among viridans group streptococci, we retrospectively examined 50 viridans group streptococcal isolates recovered from patients with infective endocarditis over 3 decades. Resistance rates (percent resistant isolates 1971 to 1986 and 1994 to 2002) were as follows: levofloxacin, 0 and 9; penicillin and clindamycin, 0 and 4; and erythromycin and azithromycin, 11 and 26, respectively.
Pharmacokinetics of Indinavir at 800, 600, and 400 Milligrams Administered with Ritonavir at 100 Milligrams and Efavirenz in Ethnic Chinese Patients Infected with Human Immunodeficiency Virus
Authors: Lee Lawrence S. , Panchalingam Anushia , Yap Marline C. , Paton Nicholas I. 
Published: October 2004

ABSTRACT
We assessed the pharmacokinetics of three different doses of indinavir in five patients. All doses achieved trough concentrations above efficacy thresholds. Toxic trough concentrations were observed in all patients receiving 800 mg, in two patients receiving 600 mg, and in none receiving 400 mg. Indinavir at 400 mg may be efficacious and less toxic in patients taking ritonavir and efavirenz.
Comparison of Simultaneous Splenic Sample PCR with Blood Sample PCR for Diagnosis and Treatment of Experimental
Ehrlichia canis
Infection
Authors: Harrus Shimon , Kenny Martin , Miara Limor , Aizenberg Itzhak , Waner Trevor , Shaw Susan 
Published: October 2004

ABSTRACT
This report presents evidence that dogs recover from acute canine monocytic ehrlichiosis (CME) after 16 days of doxycycline treatment (10 mg/kg of body weight every 24 h). Blood PCR was as valuable as splenic aspirate PCR for early diagnosis of acute CME. Splenic aspirate PCR was, however, superior to blood PCR for the evaluation of ehrlichial elimination.
SYNCHRONIZING NONAUTONOMOUS CHAOTIC SYSTEMS WITHOUT PHASE-LOCKING
Authors: WAH WU CHAI , ZHONG GUO-QUN , CHUA LEON O. 
Published: October 2004

Pecora and Carroll1 have shown how two nonautonomous chaotic circuits driven by periodic forcing can be synchronized using the master-slave driving principle. However, in their scheme, the periodic forcing in both circuits needs to be phase-locked through some additional circuitry for the system to synchronize. In this paper, we show two ways in which this can be avoided. In the first scheme, the two circuits are connected in a master-slave driving configuration and the periodic forcing is included in the driving signal such that it eliminates the need for the slave circuit to have an external periodic forcing signal. In addition, we can recover the periodic forcing signal at the slave circuit. In the second scheme, the two circuits are connected in a mutual coupling configuration. The two circuits will synchronize regardless of what the periodic forcing signals of the two circuits are. In particular, the two periodic forcing signals could have different phases, different frequencies, or different shapes. We discuss two interpretations of these synchronization schemes. First, we consider them as communication systems when the periodic forcing signal is replaced by a properly encoded information signal. We illustrate this in a physical circuit implementation. Second, we consider them as synchronization schemes for nonidentical systems by considering the external forcing signal as an error signal due to the difference between the two systems.