bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survey of Susceptibilities of
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Moraxella catarrhalis
Isolates to 26 Antimicrobial Agents: a Prospective U.S. Study
Authors: Thornsberry C. , Ogilvie P. T. , Holley H. P. , Sahm D. F. 
Published: October 2018

ABSTRACT

An antimicrobial susceptibility surveillance study of
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Moraxella catarrhalis
isolates was performed during the winter of 1996–1997 in order to determine their susceptibilities to 5 fluoroquinolones and 21 other antimicrobial agents. Broth microdilution MICs were determined for 2,752 isolates from 51 U.S. medical centers. Of the 1,276
S. pneumoniae
isolates, 64% were susceptible, 17% were intermediate, and 19% were highly resistant to penicillin. On the basis of the MICs at which 90% of isolates are inhibited and modal MICs, the hierarchy of the five fluoroquinolones from most to least active was grepafloxacin > sparfloxacin > levofloxacin = ciprofloxacin > ofloxacin. For
S. pneumoniae
isolates for which penicillin MICs were elevated, the MICs of the cephalosporins, macrolides, clindamycin, tetracycline, and trimethoprim-sulfamethoxazole were also elevated, but the MICs of the fluoroquinolones, vancomycin, and rifampin were not. The prevalence of penicillin-susceptible pneumococci varied by U.S. Bureau of the Census region (range, 44% in the East South Central region to 75% in the Pacific region). In addition,
S. pneumoniae
isolates from blood were significantly more susceptible to penicillin than those from respiratory, ear, or eye specimens, and pneumococci from patients ≤2 years old were significantly more resistant to penicillin than those from older patients (by chi-square analysis,
P
< 0.05). β-Lactamase was produced by 35% of
H. influenzae
isolates and 93% of
M. catarrhalis
isolates, resulting in increased MICs of amoxicillin and certain cephalosporins. We noted that the antimicrobial resistance patterns of
S. pneumoniae
isolates, which correlate with the penicillin susceptibility phenotype, vary by site of infection, age group of the patient, and geographic source of the isolate.
Effects of Genes Encoding Resistance to Streptogramins A and B on the Activity of Quinupristin-Dalfopristin againstEnterococcus faecium
Authors: Bozdogan Bülent , Leclercq Roland 
Published: October 2018

ABSTRACTQuinupristin-dalfopristin is a streptogramin combination active against multiply resistantEnterococcus faecium. Among 45E. faeciumisolated from patients in various French hospitals, only two strains were intermediate (MIC = 2 μg/ml) and one,E. faeciumHM1032, was resistant (MIC = 16 μg/ml) to quinupristin-dalfopristin, according to British Society for Antimicrobial Chemotherapy and National Committee for Clinical Laboratory Standards approved breakpoints. The latter strain contained thevgbandsatAgenes responsible for hydrolysis or acetylation of quinupristin and dalfopristin, respectively, and anermBgene (also previously referred to asermAM) encoding a ribosomal methylase. The two intermediate strains had an LSAphenotype characterized by resistance to lincomycin (L), increased MICs (≥8 μg/ml) of dalfopristin (streptogramin A [SA]), and susceptibility to erythromycin and quinupristin. This phenotype was also detected in eight other strains susceptible to quinupristin-dalfopristin. No genes already known and conferring resistance to dalfopristin by acetylation or active efflux were detected in these LSAstrains. Nineteen other strains resistant to erythromycin but susceptible to the quinupristin-dalfopristin combination displayed elevated MICs of quinupristin after induction (from 16 to >128 μg/ml) and containedermBgenes. The effects ofermB,vgb, andsatAgenes on the activity of the streptogramin combination were tested by cloning these genes individually or in various combinations in recipient strains susceptible to quinupristin-dalfopristin,E. faeciumHM1070 andStaphylococcus aureusRN4220. The presence of both thesatAandvgbgenes (regardless of the presence of anermBgene) was necessary to confer full quinupristin-dalfopristin resistance to the host. The same genetic constructs were introduced intoE. faeciumBM4107 which displays a LSAphenotype. Addition of thesatAorvgbgene to this LSAbackground conferred resistance to quinupristin-dalfopristin.
Pharmacokinetics of a Once-Daily Oral Dose of Moxifloxacin (Bay 12-8039), a New Enantiomerically Pure 8-Methoxy Quinolone
Authors: Sullivan John T. , Woodruff Marilyn , Lettieri John , Agarwal Vipin , Krol George J. , Leese Philip T. , Watson Susan , Heller Allen H. 
Published: October 2018

ABSTRACT

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (
n
= 10) or a placebo once daily (
n
= 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (
C
max
) and the area under the concentration-time curve from 0 to 24 h (AUC
0–24
) were 3.4 mg/liter and 30.2 mg · h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg · h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for
Streptococcus pneumoniae
throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean
C
max
/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and
C
max
/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.
Azithromycin Activities against
Orientia tsutsugamushi
Strains Isolated in Cases of Scrub Typhus in Northern Thailand
Authors: Watt George , Kantipong Pacharee , Jongsakul Krisada , Watcharapichat Pochaman , Phulsuksombati Duangporn 
Published: October 2018

ABSTRACT

Azithromycin was given to mice and humans infected with strains of
Orientia tsutsugamushi
from northern Thailand, where drug-resistant scrub typhus occurs. Azithromycin and doxycycline yielded comparable mouse survival rates (73 and 79%, respectively;
P
> 0.5). Symptoms, signs, and fever in two pregnant women abated rapidly with azithromycin. Prospective human trials are needed.
Efficacy of the Triazole SCH 56592 against
Leishmania amazonensis
and
Leishmania donovani
in Experimental Murine Cutaneous and Visceral Leishmaniases
Authors: Al-Abdely Hail M. , Graybill John R. , Loebenberg David , Melby Peter C. 
Published: October 2018

ABSTRACT

Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with
Leishmania amazonensis
and visceral infection with
Leishmania donovani
in BALB/c mice. Mice were infected in the ear pinna and tail with
L. amazonensis
promastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 ± 0.12, 0.11 ± 0.06, 0.17 ± 0.07, and 0.19 ± 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (
P
= 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to
L. donovani
infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to
L. amazonensis
infection and, to a lesser degree, against visceral leishmaniasis due to
L. donovani
infection in susceptible BALB/c mice.
Proton-Pumping-ATPase-Targeted Antifungal Activity of a Novel Conjugated Styryl Ketone
Authors: Manavathu Elias K. , Dimmock Jonathan R. , Vashishtha Sarvesh C. , Chandrasekar Pranatharthi H. 
Published: October 2018

ABSTRACT

NC1175 (3-[3-(4-chlorophenyl)-2-propenoyl]-4-[2-(4-chlorophenyl)vinylene]-1-ethyl-4-piperidinol hydrochloride) is a novel thiol-blocking conjugated styryl ketone that exhibits activity against a wide spectrum of pathogenic fungi. Incubation of NC1175 with various concentrations of cysteine and glutathione eliminated its antifungal activity in a concentration-dependent fashion. Since NC1175 is a lipophilic compound that has the potential to interact with cytoplasmic membrane components, we examined its effect on the membrane-located proton-translocating ATPase (H
+
-ATPase) of yeast (
Candida albicans
,
Candida krusei
,
Candida guilliermondii
,
Candida glabrata
, and
Saccharomyces cerevisiae
) and
Aspergillus
(
Aspergillus fumigatus
,
Aspergillus niger
,
Aspergillus flavus
, and
Aspergillus nidulans
) species. The glucose-induced acidification of external medium due to H
+
-ATPase-mediated expulsion of intracellular protons by these fungi was measured in the presence of several concentrations of the drug. NC1175 (12.5 to 50 μM) inhibited acidification of external medium by
Candida
,
Saccharomyces
, and
Aspergillus
species in a concentration-dependent manner. Vanadate-inhibited hydrolysis of ATP by membrane fractions of
C. albicans
was completely inhibited by 50 μM NC1175, suggesting that the target of action of NC1175 in these fungi may include H
+
-ATPase.
Oral Bioavailability and Pharmacokinetics of Trovafloxacin in Patients with AIDS
Authors: Lacy Melinda K. , Nicolau David P. , Nightingale Charles H. , Geffken Amy , Teng Renli , Vincent John , Quintiliani Richard 
Published: October 2018

ABSTRACTTrovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.
Population Pharmacokinetics of Lamivudine in Adult Human Immunodeficiency Virus-Infected Patients Enrolled in Two Phase III Clinical Trials
Authors: Moore Katy H. P. , Yuen Geoffrey J. , Hussey Elizabeth K. , Pakes Gary E. , Eron Joseph J. , Bartlett John A. 
Published: October 2018

ABSTRACT

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4
+
cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4
+
cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.
Beneficial Effect of Adjunctive Azithromycin in Treatment of Mucoid
Pseudomonas aeruginosa
Pneumonia in the Murine Model
Authors: Nicolau David P. , Banevicius Mary Anne , Nightingale Charles H. , Quintiliani Richard 
Published: October 2018

ABSTRACT

While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of
Pseudomonas aeruginosa
.
The Thiocarboxanilide Nonnucleoside Inhibitor UC781 Restores Antiviral Activity of 3′-Azido-3′-Deoxythymidine (AZT) against AZT-Resistant Human Immunodeficiency Virus Type 1
Authors: Borkow Gadi , Arion Dominique , Wainberg Mark A. , Parniak Michael A. 
Published: October 2018

ABSTRACT

N
-[4-Chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide (UC781) is an exceptionally potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We found that a 1:1 molar combination of UC781 and 3′-azido-3′-deoxythymidine (AZT) showed high-level synergy in inhibiting the replication of AZT-resistant virus, implying that UC781 can restore antiviral activity to AZT against AZT-resistant HIV-1. Neither the nevirapine plus AZT nor the 2′,5′-bis-
O
-(
t
-butyldimethylsilyl)-3′-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide plus AZT combinations had this effect. Studies with purified HIV-1 reverse transcriptase (from a wild type and an AZT-resistant mutant) showed that UC781 was a potent inhibitor of the pyrophosphorolytic cleavage of nucleotides from the 3′ end of the DNA polymerization primer, a process that we have proposed to be critical for the phenotypic expression of AZT resistance. Combinations of UC781 plus AZT did not act in synergy to inhibit the replication of either wild-type virus or UC781-resistant HIV-1. Importantly, the time to the development of viral resistance to combinations of UC781 plus AZT is significantly delayed compared to the time to the development of resistance to either drug alone.
Stage-Specific Activity of Pentavalent Antimony against
Leishmania donovani
Axenic Amastigotes
Authors: Ephros Moshe , Bitnun Ari , Shaked Pninit , Waldman Ella , Zilberstein Dan 
Published: October 2018

ABSTRACT

The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of
Leishmania donovani
to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37°C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant
L. donovani
mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in
Leishmania tarentolae
. These data show that
L. donovani
susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.
Escherichia coli
ATCC 35218 as a Quality Control Isolate for Susceptibility Testing of
Haemophilus influenzae
with Haemophilus Test Medium
Authors: Butler D. L. , Jakielaszek C. J. , Miller L. A. , Poupard J. A. 
Published: October 2018

ABSTRACT

Current National Committee for Clinical Laboratory Standards (NCCLS) susceptibility guidelines for quality control testing with
Haemophilus influenzae
do not include a β-lactamase-producing strain that could detect the deterioration of the β-lactamase inhibitor components of amoxicillin-clavulanic acid, ampicillin-sulbactam, and piperacillin-tazobactam. The objective of the study was to determine if comparable quality control results for
Escherichia coli
ATCC 35218, a β-lactamase-producing strain, would be produced for the three β-lactam–β-lactamase inhibitor agents with Haemophilus test medium and Mueller-Hinton medium. The criteria used in this study to determine if Haemophilus test medium was acceptable for quality control testing of
E. coli
ATCC 35218 was that 100% of the results obtained with an antimicrobial agent-methodology combination needed to be within the acceptable NCCLS ranges established with Mueller-Hinton medium. The MIC testing results obtained by the broth microdilution and E-test methods with amoxicillin-clavulanic acid and piperacillin-tazobactam were all within the NCCLS ranges; however, the results obtained with ampicillin-sulbactam by both methods were not within the NCCLS ranges. Acceptable results were obtained by the disk diffusion methodology with ampicillin-sulbactam and piperacillin-tazobactam but not with amoxicillin-clavulanic acid. When performing susceptibility testing with
H. influenzae
with the β-lactam–β-lactamase inhibitors, in addition to quality control testing with
H. influenzae
ATCC 49247, testing of
E. coli
ATCC 35218 on Haemophilus test medium is an effective way to monitor the β-lactamase inhibitors in some antimicrobial agent-methodology combinations.
In Vivo Emergence of Multidrug-Resistant Mutants ofPseudomonas aeruginosaOverexpressing the Active Efflux System MexA-MexB-OprM
Authors: Ziha-Zarifi Isabelle , Llanes Catherine , Köhler Thilo , Pechere Jean-Claude , Plesiat Patrick 
Published: October 2018

ABSTRACTDuring a 6-month period, 21 pairs ofPseudomonas aeruginosaisolates susceptible (pretherapy) and resistant (posttherapy) to antipseudomonal β-lactam antibiotics were isolated from hospitalized patients. In vivo emergence of β-lactam resistance was associated with the overexpression of AmpC β-lactamase in 10 patients. In the other 11 patients, the posttherapy isolates produced only low, basal levels of β-lactamase and had increased levels of resistance to a variety of non-β-lactam antibiotics (e.g., quinolones, tetracyclines, and trimethoprim) compared with the levels of β-lactamase production and resistance of their pretherapy counterparts. These data suggested the involvement of the MexA-MexB-OprM active efflux system in the multidrug resistance phenotype of the posttherapy strains. Immunoblotting of the outer membrane proteins of these 11 bacterial pairs with a specific polyclonal antibody raised against OprM demonstrated the overexpression of OprM in all the posttherapy isolates. To determine whether mutations inmexR, the regulator gene of themexA-mexB-oprMefflux operon, could account for the overproduction of the efflux system, sequencing experiments were carried out with the 11 bacterial pairs. Eight posttherapy isolates were found to contain insertions or deletions that led to frameshifts in the coding sequences ofmexR. Two resistant strains had point mutations inmexRthat yielded single amino acid changes in the protein MexR, while another strain did not show any mutation inmexRor in the promoter region upstream ofmexR. Introduction of a plasmid-encoded wild-typemexRgene into five posttherapy isolates partially restored the susceptibility of the bacteria to selected antibiotics. These results indicate that in the course of antimicrobial therapy multidrug-resistant active efflux mutants overexpressing the MexA-MexB-OprM system may emerge as a result of mutations in themexRgene.
Activities of Newer Fluoroquinolones against
Streptococcus pneumoniae
Clinical Isolates Including Those with Mutations in the
gyrA
,
parC
, and
parE
Loci
Authors: Jorgensen J. H. , Weigel L. M. , Ferraro M. J. , Swenson J. M. , Tenover F. C. 
Published: October 2018

ABSTRACT

Resistance to fluoroquinolone (FQ) antibiotics in
Streptococcus pneumoniae
has been attributed primarily to specific mutations in the genes for DNA gyrase (
gyrA
and
gyrB
) and topoisomerase IV (
parC
and
parE
). Resistance to some FQs can result from a single mutation in one or more of the genes encoding these essential enzymes. A group of 160 clinical isolates of pneumococci was examined in this study, including 36 ofloxacin-resistant isolates (MICs, ≥8 μg/ml) recovered from patients in North America, France, and Belgium. The susceptibilities of all isolates to clinafloxacin, grepafloxacin, levofloxacin, sparfloxacin, and trovafloxacin were examined by the National Committee for Clinical Laboratory Standards reference broth microdilution and disk diffusion susceptibility testing methods. Among the ofloxacin-resistant strains, 32 of 36 were also categorized as resistant to levofloxacin, 35 were resistant to sparfloxacin, 29 were resistant to grepafloxacin, and 19 were resistant to trovafloxacin. In vitro susceptibility to clinafloxacin appeared to be least affected by resistance to the other FQs. Eight isolates with high- and low-level resistance to the newer FQs were selected for DNA sequence analysis of the quinolone resistance-determining regions (QRDRs) of
gyrA
,
gyrB
,
parC
, and
parE
. The DNA and the inferred amino acid sequences of the resistant strains were compared with the analogous sequences of reference strain
S. pneumoniae
ATCC 49619 and FQ-susceptible laboratory strain R6. Reduced susceptibilities to grepafloxacin and sparfloxacin (MICs, 1 to 2 μg/ml) and trovafloxacin (MICs, 0.5 to 1 μg/ml) were associated with either a mutation in
parC
that led to a single amino acid substitution (Ser-79 to Phe or Tyr) or double mutations that involved the genes for both GyrA (Ser-81 to Phe) and ParE (Asp-435 to Asn). High-level resistance to all of the compounds except clinafloxacin was associated with two or more amino acid substitutions involving both GyrA (Ser-81 to Phe) and ParC (Ser-79 to Phe or Ser-80 to Pro and Asp-83 to Tyr). No mutations were observed in the
gyrB
sequences of resistant strains. These data indicate that mutations in pneumococcal
gyrA
,
parC
, and
parE
genes all contribute to decreased susceptibility to the newer FQs, and genetic analysis of the QRDR of a single gene, either
gyrA
or
parC
, is not predictive of pneumococcal resistance to these agents.