bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections
Authors: Dalhoff A. , Schubert S. , Vente A. 
Published: February 2017

ABSTRACT

The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-β-lactamase (ESBL)-producing
Enterobacteriaceae
isolates were compared. Since quinolones lose activity in acidic media, and particularly in urine, their activities were tested in parallel under conventional conditions and in acidic artificial urine. For this purpose, TEM- and SHV-type ESBL-producing
Escherichia coli
and
Klebsiella pneumoniae
strains and their wild-type counterparts were exposed in a modified Grasso model to simulated concentrations of drugs in serum and urine following oral doses of either finafloxacin at 800 mg once a day (q.d.), immediate-release ciprofloxacin at 500 mg twice a day (b.i.d.), extended-release ciprofloxacin at 1,000 mg q.d., or levofloxacin at 500 or 750 mg q.d. The concentrations of the drugs in urine were fitted by compartmental modeling. Bacteria were cultivated in Mueller-Hinton broth (MHB) at pH 7.2 or 5.8 or in artificial urine at pH 5.8. Bacteria were counted every 2 h until 10 h and at 24 h; the areas under the bacterial-count–versus–time curves were calculated. It was found that finafloxacin eliminated all strains within 2 h under all the conditions studied. At all doses studied, ciprofloxacin and levofloxacin were highly active against wild-type strains in MHB at pH 7.2 but lost activity in MHB, and particularly in urine, at pH 5.8. Viable counts of ESBL producers were reduced for 6 to 8 h by 3 log
10
titers, but the bacteria regrew thereafter. Ciprofloxacin and levofloxacin were almost inactive against the SHV producer grown in artificial urine. We conclude that pharmacodynamic models using artificial urine may mirror the physiology of urinary tract infections more closely than those using conventional media. In contrast to ciprofloxacin and levofloxacin, finafloxacin gained activity in this model at an acidic pH, maintained activity in artificial urine, and was active against TEM and SHV producers.
Characterization of the pJB12 Plasmid from Pseudomonas aeruginosa Reveals Tn
6352
, a Novel Putative Transposon Associated with Mobilization of the
bla
VIM-2
-Harboring In58 Integron
Authors: Botelho João , Grosso Filipa , Peixe Luísa 
Published: February 2017

ABSTRACT

The
bla
VIM-2
-carrying In58 integron has been linked to a chromosomal location in different bacterial species, including
Pseudomonas aeruginosa
. This work reports the first fully sequenced In58-harboring plasmid, which is significantly different from the two previously identified
bla
VIM-2
-carrying plasmids in
P. aeruginosa
.
bla
VIM-2
might have been acquired by transposition of Tn
6352
, a novel transposon composed of the In58 and IS
Pa17
elements. The recognition of similar inverted repeat (IR) sites by IS
Pa17
reveals a common mobilization process associated with acquisition of the
bla
VIM-2
and
bla
VIM-1
genes.
In Vitro
Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir
Authors: Ng Teresa I. , Krishnan Preethi , Pilot-Matias Tami , Kati Warren , Schnell Gretja , Beyer Jill , Reisch Thomas , Lu Liangjun , Dekhtyar Tatyana , Irvin Michelle , Tripathi Rakesh , Maring Clarence , Randolph John T. , Wagner Rolf , Collins Christine 
Published: February 2017

ABSTRACT

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC
50
) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC
50
for the respective replicon. With pibrentasvir at 10-fold over the respective EC
50
, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC
50
, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.
Insight into the Diversity of Penicillin-Binding Protein 2x Alleles and Mutations in Viridans Streptococci
Authors: van der Linden Mark , Otten Julia , Bergmann Carina , Latorre Cristina , Liñares Josefina , Hakenbeck Regine 
Published: February 2017

ABSTRACT

The identification of commensal streptococci species is an everlasting problem due to their ability to genetically transform. A new challenge in this respect is the recent description of
Streptococcus pseudopneumoniae
as a new species, which was distinguished from closely related pathogenic
S. pneumoniae
and commensal
S. mitis
by a variety of physiological and molecular biological tests. Forty-one atypical
S. pneumoniae
isolates have been collected at the German National Reference Center for Streptococci (GNRCS). Multilocus sequence typing (MLST) confirmed 35 isolates as the species
S. pseudopneumoniae
. A comparison with the
pbp2x
sequences from 120 commensal streptococci isolated from different continents revealed that
pbp2x
is distinct among penicillin-susceptible
S. pseudopneumoniae
isolates. Four penicillin-binding protein x (PBPx) alleles of penicillin-sensitive
S. mitis
account for most of the diverse sequence blocks in resistant
S. pseudopneumoniae
,
S. pneumoniae
, and
S. mitis
, and
S. infantis
and
S. oralis
sequences were found in
S. pneumoniae
from Japan. PBP2x genes of the family of mosaic genes related to
pbp2x
in the
S. pneumoniae
clone Spain
23F
-1 were observed in
S. oralis
and
S. infantis
as well, confirming its global distribution. Thirty-eight sites were altered within the PBP2x transpeptidase domains of penicillin-resistant strains, excluding another 37 sites present in the reference genes of sensitive strains. Specific mutational patterns were detected depending on the parental sequence blocks, in agreement with distinct mutational pathways during the development of beta-lactam resistance. The majority of the mutations clustered around the active site, whereas others are likely to affect stability or interactions with the C-terminal domain or partner proteins.
Structural Analysis of Mycobacterium tuberculosis Homologues of the Eukaryotic Proteasome Assembly Chaperone 2 (PAC2)
Authors: Bai Lin , Jastrab Jordan B. , Isasa Marta , Hu Kuan , Yu Hongjun , Gygi Steven P. , Darwin K. Heran , Li Huilin 
Published: February 2017

ABSTRACT

A previous bioinformatics analysis identified the
Mycobacterium tuberculosis
proteins Rv2125 and Rv2714 as orthologs of the eukaryotic proteasome assembly chaperone 2 (PAC2). We set out to investigate whether Rv2125 or Rv2714 can function in proteasome assembly. We solved the crystal structure of Rv2125 at a resolution of 3.0 Å, which showed an overall fold similar to that of the PAC2 family proteins that include the archaeal PbaB and the yeast Pba1. However, Rv2125 and Rv2714 formed trimers, whereas PbaB forms tetramers and Pba1 dimerizes with Pba2. We also found that purified Rv2125 and Rv2714 could not bind to
M. tuberculosis
20S core particles. Finally, proteomic analysis showed that the levels of known proteasome components and substrate proteins were not affected by disruption of Rv2125 in
M. tuberculosis
. Our work suggests that Rv2125 does not participate in bacterial proteasome assembly or function.

IMPORTANCE
Although many bacteria do not encode proteasomes,
M. tuberculosis
not only uses proteasomes but also has evolved a posttranslational modification system called pupylation to deliver proteins to the proteasome. Proteasomes are essential for
M. tuberculosis
to cause lethal infections in animals; thus, determining how proteasomes are assembled may help identify new ways to combat tuberculosis. We solved the structure of a predicted proteasome assembly factor, Rv2125, and isolated a genetic Rv2125 mutant of
M. tuberculosis
. Our structural, biochemical, and genetic studies indicate that Rv2125 and Rv2714 do not function as proteasome assembly chaperones and are unlikely to have roles in proteasome biology in mycobacteria.
PHARMACOKINETICS OF RIFABUTIN IN COMBINATION WITH LOPINAVIR-RITONAVIR IN ADULT PATIENTS WITH HIV AND TUBERCULOSIS CO-INFECTION IN BURKINA FASO
Authors: Ouedraogo Henri Gautier , Matteelli Alberto , Regazzi Mario , Tarnagda Grissoum , Villani Paola , Sulis Giorgia , Diagbouga Serge , Roggi Alberto , Giorgetti Francesco , Kouanda Seni 
Published: February 2017

BackgroundThis study aimed to assess the pharmacokinetic profile of rifabutin (RBT) given at 150 mg or 300 mg every other day (EOD) in tuberculosis (TB)-HIV co-infected adult patients.MethodsThis is a pharmacokinetic prospective, pilot, open, randomised study of two doses of RBT in combination with lopinavir/ritonavir among HIV−TB patients in Burkina. Sixteen patients were randomised in two arms: TB treatment consisting HZE standard doses in association with RBT150 mg EOD (arm A, 8 patients) or RBT300 mg EOD (arm B, 8 patients) in combination with lopinavir/ritonavir. RBT plasma concentrations were evaluated after two weeks of combined HIV and TB treatment. Samples were collected at pre-dosing and at 1, 2, 3, 4, 6, 8 and12 hours after drug ingestion to measure plasma drug concentration using HPLC–MS/MS assay.ResultsThe mean Cmax and AUC in the RBT 150 mg arm (Cmax=0.35±0,18 µg/mL, AUC(0–24)=3.94±2,1 µg.h/mL) were significantly lower (p=0.01) than those of the RBT 300 mg arm (Cmax=0.75±0.54 µg/mL AUC(0–24)=7.1±2.7 µg.h/mL). There was no significant difference in Tmax (Tmax=3.44±2.01 hoursvsTmax=3.86±2.04 hours) p=0.687. RBT follows linear kinetics and no significant differences were apparent in the mean oral clearance (CL/F) estimates (p=0.683), which were dose independent and similar for the 2 assessment doses. Five of 8 patients in RBT150 mg arm had a Cmax below plasma therapeutic limit (<0.3 µg/ml). All patients in RBT 300 mg arm had a higher Cmax than this limit. Also, at 48 hours of drug ingestion, all patients in the RBT 300 mg arm (8/8) had a mycobacterial minimum inhibitory concentration (MIC) above the limit (>0.06 µg/mL) compared with 4 of 8 patients in the RBT150 mg arm. The means Cmax, AUC (0–24) and Tmax of 25-O-desacetyl rifabutin of the RBT 300 mg arm were increased by 100% and 50% respectively compared to the RBT150 mg arm.ConclusionsThis study confirmed that the dose of rifabutin 150 mg three times a week in combination with lopinavir/ ritonavir is inadequate and could lead to the selection of rifamycin-resistant mycobacteria.
HEPATITIS B VIRUS CO-INFECTION IS ASSOCIATED WITH INCREASED ALL-CAUSE MORTALITY AMONG HIV-INFECTED ADULTS ON TENOFOVIR-DISOPROXIL-FUMARATE CONTAINING ANTIRETROVIRAL THERAPY IN LUSAKA, ZAMBIA
Authors: Vinikoor Michael , Chilengi Roma , Mulenga Lloyd , Kaayunga Callistus , Zyambo Zude , Davies Mary-Ann , Egger Matthias , Wandeler Gilles 
Published: February 2017

MethodsWe prospectively enrolled HIV-infected treatment naïve adults in Lusaka, Zambia. At enrolment, we recorded patient's demographics, body mass index (BMI), WHO clinical stage, CD4+ count, and hepatitis B surface antigen (HBsAg) status. In HBsAg-positive patients we measured HBV viral loads (VL; Roche, COBAS® AmpliPrep/COBAS® Taqman® Assay, Pleasanton, California). We defined active HBV co-infection as having an HBV VL320 IU/ml. TDF-based ART was the preferred first-line regimen. Follow-up visits occurred per national guidelines and we used phone and community tracing to optimise retention. Deaths were ascertained by clinic, family member, or community health worker report and losses to follow-up (LFTU) were defined as absences from clinic for 6+ months. Using multivariable Cox regression, we assessed the mortality risk among patients with HBV co-infection, adjusting for age, sex, WHO stage, BMI, and CD4+ count.ResultsDuring 2013–2014, 822 patients were enrolled and analysed at 1 year after ART initiation. Among this group, 438 (53.1%) were women, median age was 34 years (interquartile range, 29–40), 367 (44.8%) had WHO stage 3 or 4, 229 (28.2%) had BMI <18.5, and median baseline CD4+ 224 cells/ mm3. Of 126 HBsAg-positive individuals, 81 had active HBV infection. During the first year on ART, 48 patients died, 19 transferred out or withdrew, and 52 were LTFU. Those with HBV co-infection had twice the risk of death (adjusted hazard ratio, 2.23, 95% CI: 1.07–4.65) after adjustment for covariates.ConclusionsIn Southern Africa, HBV co-infection is a mortality risk factor and these patients should be diagnosed and those with replicating virus may need closer monitoring. Further investigation of the causes of death in HIV-HBV patients is needed.
CAN HIV TREATMENTS INFORM OTHER CONTEXTS? A TRIAL OF AN ADDITIONAL INDICATION FOR CO-TRIMOXAZOLE PROPHYLAXIS
Authors: Ngari Moses , Thitiri Johnstone , Mwalekwa Laura , Fegan Greg , Berkley James 
Published: February 2017

BackgroundCo-trimoxazole prophylaxis is part of HIV management of opportunistic infections. However, it is not known if co-trimoxazole prophylaxis can prevent opportunistic infections among other vulnerable population such as people with complicated severe acute malnutrition (SAM). It is unclear if and how nutritional recovery may reduce susceptibility to infectious diseases like pneumonia with co-trimoxazole prophylaxis. We share secondary analysis results of multicentre, double-blinded, randomised clinical trial (ClinicalTrials. gov, numberNCT00934492) of daily co-trimoxazole prophylaxis among HIV non-infected children with SAM in Kenya.MethodsWe recruited 1781 hospitalised SAM children and randomised to either daily co-trimoxazole prophylaxis or matching placebo for six months and followed up for 12 months. Our outcome of interest was risk of subsequent pneumonia after index admission discharge, defined using the WHO guidelines. To determine changing susceptibility after discharge, cox regression model with monthly weight-for-height and height-for-age z-scores as time-varying covariates were used to identify risk factors of developing pneumonia.ResultsOverall, 257 children died, 122 (14%) among the co-trimoxazole group and 135 (15%) of placebo group; Hazard ratio (HR) 0.90 (95% CI: 0.71−1.16, p=0.43). There were 1257 episodes of pneumonia, 603 (21%) among co-trimoxazole group and 654 (22%) among placebo; HR 0.93 (95% CI:0.79−1.08, p=0.34) during 1556.6 child-years of observation (cyo). The monthly incidence rate for pneumonia and severe pneumonia declined over time (p=0.002 & p=0.001). Young age, urban residence, index admission with clinical signs of rickets and severe pneumonia, were associated with subsequent pneumonia. Index admission with diarrhoea and monthly weight-for-length z-score had protective effect. Protective effect of improving monthly anthropometric measures were evident from month two onwards. Proportion of pneumonia progressing to severe form declined with time (p=0.01) but there was no evidence case fatality ratios changed over time (p=0.41).ConclusionsImproving nutritional status during recovery correlates directly with reduced susceptibility, but not with case fatality of pneumonia.
PREVALENCE AND PREDISPOSING FACTORS TO INTESTINAL PARASITIC INFECTIONS IN HIV/AIDS PATIENTS IN FAKO DIVISION OF CAMEROON
Authors: Nsagha Dickson 
Published: February 2017

BackgroundUnderstanding the epidemiology of intestinal parasitic infections is essential for the effective management of HIV infection in areas where intestinal parasites are also endemic. Data on the prevalence of intestinal parasitic infections in people living with HIV/AIDS in Cameroon are scarce. This study was designed to determine the prevalence of intestinal parasitic infections, as well as assess the predisposing factors for the infections in HIV/AIDS patients in Fako division of Cameroon.MethodsStool specimen was collected from consented participants and examined for ova, cysts, larvae or oocytes using the Kato-Katz, Formalin-Ether Concentration, Modified Ziehl-Neelsen and Modified field staining techniques. Statistical analyses performed included the Chi-square test and logistic regression.ResultsAt the end of the study, 300 participants were enrolled, the majority being females 236 (78.6%). The participants were between 21–70 years (mean±SD=40±10) of age. The overall prevalence of intestinal parasites was 82.6% (95% CI: 78.4–87.0). The prevalence of infection was associated with age, being more prevalent in the age group 51–60 years (p=0.032). Intestinal protozoa were more prevalent than intestinal helminthes (74.3%vs11.3%). The parasites isolated included:Cryptosporidium parvum(44.0%),Blastocystis hominis(25.0%),Microsporidium spp.(21.0%),Entamoeba histolytica(7.3%),Ascaris lumbricoïdes(4.3%),Isospora belli(4.3%),Trichuris trichiura(2.3%), hookworm (2.7%),Hymenolepis nana(1.3%),Strongyloïdes stercoralis(0.7%),Cyclospora cayetatensis(3.7%) andGiardia lamblia(3.3%). The predisposing factors for infection with intestinal parasites included poor educational background (OR=0.33, p=0.02), unskilled worker (OR=0.27, p=0.04), a well as source of drinking water (OR=2.6, p=0.03), and living with cats as pets (OR=3.06, p=0.01).ConclusionsA very high prevalence of intestinal parasitic infections was observed in people living with HIV/AIDS. Routine screening for intestinal parasites should be instituted as part of HIV care in Fako division of Cameroon to improve the management of HIV/AIDS.
FACTORS AFFECTING ANTIRETROVIRAL DRUG ADHERENCE AMONG HIV ADULT PATIENTS ATTENDING HIV CLINIC AT THE UNIVERSITY TEACHING HOSPITAL IN LUSAKA
Authors: Chirwa Uchizi , Michelo Charles , Dambe Rosalia , Hamoonga Raymond 
Published: February 2017

BackgroundEffectiveness of anti-retroviral therapy (ART) requires strict adherence. Adherence ≥95% achieves optimum therapeutic levels and reduces drug resistance. We sought to determine factors associated with ART adherence within the context of patient demographics and factors, and explore care treatment and support strategies used by patients and health workers.MethodsA Mixed Method Sequential Explanatory Design (MMSED) was employed to study adult patients receiving ART from the University Teaching Hospital, Lusaka. Adherence was measured by missed clinic appointments and pharmacy collections over the last six months. The quantitative method assessed 715 complete pharmacy records extracted from the dispensing tool to ascertain demographic and patient factors. Bivariate and multivariate logistic regression analysis was employed. Qualitative research involved in-depth interviews with patients and key informants.ResultsResults showed 79.4% of the patients were adherent to clinical appointments while 46.3% were adherent to pharmacy refills. Multivariate analysis showed lower adherence amongst the widowed on clinical appointments (OR=0.3; 95% CI: 0.1–0.9). The stepwise regression analysis revealed significant factors for adherence on clinical appointment and pharmacy refills for widowed, co-habiting and no education, (p=0.008, p=0.044, and p=0.018), respectively. About 80% of patients interviewed were adherent to ART.ConclusionsThe results show moderate ART adherence (80%). However, in view of the identified factors affecting adherence, concerted and collaborative efforts through effective and efficient interventions are needed to improve the adherence levels to at least ≥95%.
IMPROVING TUBERCULOSIS SCREENING AND DIAGNOSIS AMONG PEOPLE WITH HIV: UPDATES FROM THE INTENSIFIED CASE FINDING STUDY IN KISUMU COUNTY, KENYA
Authors: Wandiga Steve , Oduor Patience , Agaya Janet , Okumu Albert , Sharma Aditya , Cavanaugh Sean , Cain Kevin 
Published: February 2017

BackgroundTuberculosis (TB) is the leading opportunistic infection and cause of death among people living with HIV (PLHIV). HIV predisposes latently TB-infected people to developing TB disease. Current TB screening algorithms lack sensitivity and specificity. We sought to determine the sensitivity and specificity of conducting a two-step clinical screening and testing for latent TB infection (LTBI).MethodsWe enrolled 650 newly diagnosed HIV patients aged >7 years from HIV clinics in Kisumu County, Kenya. Study participants were screened for TB symptoms and sputum tested for smear microscopy, liquid culture and GeneXpert MTB/RIF (Xpert). Quantiferon (QFT) and tuberculin skin testing (TST) for LTBI. Positive results from liquid culture or Xpert defined a TB case. ‘Negative for TB’ was any participant with at least two negative Xpert or culture results from different specimens. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated and compared for one – and two – stage screening and stratified by QFT results.ResultsFemales were 62% of participants. TST-positive were 88 of 592 (15%); 274 of 648 (42%) were QFT-positive. TB prevalence was 15%. Screening results for one stage and second stage: 75% and 97% sensitivity, 31% and 12%, specificity, 89% and 96% NPV and 14% and 15% PPV, respectively. Screening performance stratified by QFT for sensitivity, specificity, NPV and PPV was 96%, 11%, 91% and 24% among QFT-positive.ConclusionsTwo-step versus one-step screening increases sensitivity but reduces specificity. Positive QFT result increases the PPV of two-step screening.