We performed a meta-analysis of randomized controlled trials (RCTs) comparing regimens of the same antibiotic (same dosage and same route of administration) administered for a different time period. We searched PubMed, the Cochrane Central Register of Controlled Trials and reference lists from publications, with no language restrictions.

Of the 1031 reports retrieved initially, seven RCTs, enrolling 3083 patients with AECB, met our inclusion criteria. The antimicrobials studied in these seven RCTs were quinolones, cefixime and clarithromycin. There was no difference between the short- and long-duration therapies with regard to treatment success in intention-to-treat [relative risk (RR) = 0.99, 95% confidence interval (CI) 0.95–1.03], clinically evaluable (RR = 0.99, 95% CI 0.96–1.02) or microbiologically evaluable (RR = 0.98, 95% CI 0.93–1.02) patients. Short-duration treatment, when compared with long, was associated with fewer adverse events (RR = 0.84, 95% CI 0.72–0.97).

Short-duration treatment seems to be as effective as and safer than long-duration antimicrobial treatment of patients with AECB. Additional research is required to clarify the long-term outcomes (namely the exacerbation-free interval after the resolution of an initial episode) of the compared regimens.

This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2.

Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm³, respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment.

Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell count.

Viral reverse transcriptase (RT) and protease (PR) genes from 198 antiretroviral (ARV)-naive patients diagnosed HIV-1 positive in May 2006 in Bamako and Segou were sequenced.

Although CRF02_AG was always the predominant HIV-1 subtype observed (72%), a higher genetic diversity than that in 2005 was observed. The overall prevalence of primary resistance is 11.5% in Mali in 2006, according to the 2007 IAS-USA list of mutations [nucleoside RT inhibitor (NRTI): 1.5%, non-NRTI (NNRTI): 9% and PI: 1%], and 2.5% (NRTI: 1%, NNRTI: 1.5% and PI: 0%), according to the Stanford list of mutations. There was no significant difference between 2005 and 2006 in the overall primary resistance prevalence or in the prevalence of mutations in the different ARV classes. Resistance mutations found in RT and PR genes are in agreement with the highly active antiretroviral therapy regimen available in Mali, except for V90I, V106I and A98G mutations which are associated with etravirine resistance, but polymorphic in non-B subtypes.

HIV-1 genetic diversity seems increased in Mali, but the overall HIV-1 primary resistance prevalence remains low. This is consistent with the findings from other West African countries where prevalence rates are lower than 5%. However, considering the large scaling up of ARV use in this country, it is necessary to regularly monitor the development of primary resistance in Mali.

The study includes a retrospective analysis of newly diagnosed HIV-1-infected patients presenting to eight HIV clinics in the north of England between March 2005 and March 2007. Resistance mutations were defined by IAS-USA. Predicted phenotypes were calculated by the Stanford University database.

Five hundred and fifty-eight patients were studied, of whom 394 (70.6%) had heterosexually acquired HIV and 377 (67.6%) were infected outside the UK. TDR testing was performed in 406 patients (72.8%). Thirteen of 392 viral resistance profiles (3.3%) showed genotypic TDR. There was no significant association between TDR and any demographic or risk factor or baseline CD4 count. In particular, rates of TDR were similar in white British (6/147, 4.1%) and black African (7/224, 3.1%) patients. The numbers of patients with TDR to individual drug classes were: nucleoside reverse transcriptase inhibitors, 2 (0.5%); non-nucleoside reverse transcriptase inhibitors, 7 (1.8%); and protease inhibitors, 4 (1.0%). No patients had multi-class resistance detected. Eleven patients (2.8%) were predicted to have significant phenotypic resistance to at least one drug.

In a large unselected UK cohort, with high coverage of TDR testing, the prevalence of TDR was low and is in accordance with recent data, showing a decrease in the prevalence of TDR in the UK. Differences in population mix did not appear to explain this low rate.

Class 1 and class 2 integrons were detected by PCR. The variable parts of the integrons were cloned and sequenced. Transformation and conjugation experiments were conducted to confirm a plasmid location of the integrons.

Class 1 and/or class 2 integrons, alone or in different combinations, were detected in 79 of the 417 E. coli isolates. Four trimethoprim resistance genes (dfrA1/12/14/17), five streptomycin/spectinomycin resistance genes (aadA1/2/4/5/6), two streptothricin resistance genes (estX, sat2), one gentamicin/tobramycin/kanamycin resistance gene (aadB) and one chloramphenicol resistance gene (catB3) were detected. Seven different cassette arrangements were identified within class 1 integrons: aadA1 (21 isolates), dfrA1 + aadA1 (18 isolates), dfrA17 + aadA5 (9 isolates), dfrA12 + orfF + aadA2 (8 isolates), aadB + aadA1 (1 isolate), dfrA14 + recombined aadA6 (1 isolate) and dfrA1 + catB3 + aadA4 (1 isolate). Three different cassette arrangements in class 2 integrons, dfrA1 + sat2 + aadA1 (24 isolates), estX + sat2 + aadA1 (6 isolates) and estX + sat2 + aadA1 (1 isolate), were identified. The plasmid location of class 1 and/or class 2 integrons was confirmed in 37 isolates.

Class 1 and/or class 2 integrons carrying resistance gene cassettes were detected in 18.9% of the isolates tested. This molecular analysis complements the phenotypic susceptibility testing conducted in the BfT-GermVet monitoring study and helps to explain the persistence of resistance genes even without direct selective pressure.

The qnrA, qnrB and qnrS genes were screened by a multiplex PCR-based technique from 257 non-repetitive nalidixic acid-resistant enterobacterial isolates collected from January 2000 to May 2005. Conjugation experiments were performed to determine whether the qnr-carrying plasmids were self-transferable. Genetic structures surrounding the qnr genes were analysed by PCR and cloning. The aac(6')-Ib-cr and qepA genes were screened among qnr-positive strains.

Six qnrB-like-positive isolates (2.3%) were detected, whereas no qnrA- or qnrS-positive isolates were detected. Three Escherichia coli and two Klebsiella pneumoniae isolates harboured a qnrB2 gene and a single Citrobacter freundii isolate had the qnrB8 gene. One qnrB2-positive isolate also had the extended-spectrum β-lactamase bla_CTX-M-2 gene. All these isolates also possessed chromosomal substitutions in gyrase- and topoisomerase-encoding genes, explaining their high-level resistance to quinolones.

This study constitutes the first epidemiological survey of the three known Qnr determinants among Brazilian isolates and shows their low prevalence in that country, with the qnrB2 gene being mostly identified.

Of the total 250 consecutive, non-duplicated isolates of P. aeruginosa, 55 isolates showed amikacin resistance. PCR amplification of genes for aminoglycoside (AG)-modifying enzymes [aac(3)-I, aac(3)-II/VI, aac(3)-III/IV, aac(6')-I, aac(6')-II, ant(2'')-I, ant(4')-II and aph(3')-VI], 16S rRNA methylases (rmtA, rmtB, rmtC and armA) and class 1 integrons was performed. In addition, we analysed the association of AG resistance genes with various β-lactamase genes.

In Korea, the amikacin resistance rate in P. aeruginosa was high (22%), and it varied among provinces (3.8% to 40%). Four types of AG-modifying enzyme genes [aph(3')-VI, ant(2'')-I, aac(6')-I and aac(3)-II/VI] were found in 48 isolates. Thirty-six strains harboured two or more types of enzymes, of which a combination of aph(3')-VI and ant(2'')-I was the most frequent (24/36 isolates, 66.7%). None harboured aac(3)-I, aac(3)-III/IV, aac(6')-II, ant(4')-II, rmtA, rmtB, rmtC or armA. Forty-two isolates co-harboured β-lactamase genes (mostly bla_OXA-10). A class 1 integron was detected in all but one, and all the ant(2'')-I and 26/29 bla_OXA-10 were found in it. In contrast, aph(3')-VI was not found to be associated with the class 1 integron. Considering the possibility of co-selection and dissemination, constant monitoring of resistance evolution is necessary.

Acinetobacter isolates were collected prospectively in 2005–06 from 19 diagnostic laboratories. They were identified to species level by AFLP, typed using AFLP, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing, and tested for susceptibility to 14 antimicrobials and for the presence of 20 genes associated with antimicrobial resistance.

A total of 150 Acinetobacter isolates were obtained from 56 intensive care units of 20 hospitals in 15 cities. They were identified as Acinetobacter baumannii (n = 108) or other species. A. baumannii isolates were allocated to EU clone I (n = 5), EU clone II (n = 66) or other, mostly unique genotypes. Two-thirds of the clone II isolates had nearly identical AFLP and PFGE fingerprints. As many as 85% and 88% isolates were susceptible to meropenem and imipenem (≤4 mg/L), respectively. Carbapenem MICs of ≥8 mg/L were found in 23 A. baumannii isolates, of which 20 belonged to clone II. Isolates with bla_OXA-58-like (n = 3)_, bla_OXA-24-like (n = 1) or ISAba1 adjacent to bla_OXA-51-like (n = 34) had carbapenem MICs of 2 to >16 mg/L, while those without these elements showed MICs of ≤0.5–4 mg/L. Clone II isolates varied in susceptibility to some antibiotics including carbapenems and carried 6–12 resistance genes in 17 combinations.

The emergence of Acinetobacter carbapenem resistance in the Czech Republic is associated with the spread of A. baumannii strains of EU clone II. The variation in susceptibility in these strains is likely to result from both the horizontal spread of resistance genes and differential expression of intrinsic genes.

Antibiotic susceptibility testing and N. gonorrhoeae multiantigen sequence typing (NG-MAST) were performed on all gonococcal isolates received by the Scottish Bacterial Sexually Transmitted Infections Reference Laboratory (SBSTIRL) during the study period.

AzHLR isolates were observed for the first time in 2004 and increased from 0.3% to 3.9% in 2007. AzDS declined from 2.1% to 1.3% in the same period. Taken together, AzDS and AzHLR isolates accounted for 5.2% of the gonococcal infections in Scotland in 2007. NG-MAST revealed that only a small number of sequence types (STs) contained AzHLR and AzDS isolates; these STs also included azithromycin-susceptible isolates. Most STs containing AzHLR isolates were genetically related on the basis of their por and tbpB alleles; however, demographic data suggested that they formed discrete sexual networks.

AzHLR strains of N. gonorrhoeae are increasing in Scotland. A 1 g dose of azithromycin should not be considered as an alternative antibiotic therapy for gonococcal infections. The use of azithromycin to treat chlamydia in patients co-infected with N. gonorrhoeae results in a level of azithromycin in vivo that is sublethal for N. gonorrhoeae, which may lead to resistance.

By plating bacterial cells on agar plates containing nitrofurantoin, spontaneous nitrofurantoin-resistant E. coli mutants were isolated. The fitness of susceptible and resistant strains was measured as growth rate in the presence and absence of nitrofurantoin in rich culture medium. Time–kill kinetics of the resistant mutants was compared with the susceptible strains. Resistance mutations were identified by DNA sequencing.

Spontaneous resistant mutants of initially susceptible clinical E. coli appeared with a rate of 10^–7/cell/generation, and these mutants showed a reduction in the growth rate compared with the susceptible parent strain. Similarly, comparison of a set of susceptible and resistant clinical isolates of E. coli showed that the average growth rate of the resistant mutants was ~6% lower than the susceptible strains. Furthermore, the bacterial growth rate in the presence of nitrofurantoin at therapeutic levels was greatly reduced even for nitrofurantoin-resistant mutants. The resistance-conferring mutations were identified in the nsfA and nfsB genes that encode oxygen-insensitive nitroreductases.

Nitrofurantoin resistance confers a reduction in fitness in E. coli in the absence of antibiotic. In the presence of therapeutic levels of nitrofurantoin, even resistant mutants are so disturbed in growth that they are probably unable to become enriched and establish an infection.

S. aureus ATCC 25923 was grown in increasing concentrations of ethidium bromide. The MICs of representatives of eight classes of antibiotics, eight biocides and two dyes against ATCC 25923 and its ethidium bromide-resistant progeny ATCC 25923_EtBr were determined with or without six efflux pump inhibitors (EPIs). Efflux activity in the presence/absence of EPIs was evaluated by real-time fluorometry. The presence and expression of eight EP genes were assayed by PCR and quantitative RT–PCR (qRT–PCR), respectively. Mutations in grlA, gyrA and norA promoter regions were screened by DNA sequencing.

Compared with its parental strain, ATCC 25923_EtBr was 32-fold more resistant to ethidium bromide and also more resistant to biocides and hydrophilic fluoroquinolones. Resistance to these could be reduced by the EPIs chlorpromazine, thioridazine and reserpine. Increased efflux of ethidium bromide by ATCC 25923_EtBr could be inhibited by the same EPIs. qRT–PCR showed that norA was 35-fold over-expressed in ATCC 25923_EtBr, whereas the remaining EP genes showed no significant increase in their expression. Sequencing of the norA promoter region revealed a 70 bp deletion in ATCC 25923_EtBr.

Exposure of S. aureus to quaternary compounds such as ethidium bromide results in decreased susceptibility of the organism to a wide variety of compounds, including quinolones and biocides through an efflux-mediated response, which for strain ATCC 25923 is mainly NorA-mediated. This altered expression may result from alterations in the norA promoter region.

A total of 240 nosocomial MRSA isolates obtained in 1990, 1995, 2000 and 2005 at National Taiwan University Hospital (NTUH), a hospital where chlorhexidine gluconate was used for hand hygiene for more than 20 years, were included in the study. Chlorhexidine susceptibility, molecular typing using multilocus sequence typing and distribution of the qacA/B gene of these MRSA isolates were studied.

The proportion of tested MRSA with a high MIC of chlorhexidine (≥4 mg/L) was 1.7% in 1990, 50% in 1995, 40% in 2000 and 46.7% in 2005. Among these 83 isolates with high chlorhexidine MICs, 55.4% carried the qacA/B gene. MRSA isolates carrying the qacA/B gene were first detected in 1995 and belonged to a single clone at that time. However, the qacA/B gene was detected in MRSA isolates belonging to seven different clones in 2005.

The proportion of tested MRSA isolates with high chlorhexidine MICs at NTUH increased from 1990 to 1995 and remained steady thereafter. The presence of the qacA/B gene may contribute to the spread of specific MRSA clones.

THP-1 monocytes were differentiated with phorbol myristate acetate (PMA) and compared with unstimulated cells for: (i) moxifloxacin and levofloxacin accumulation; and (ii) activity against phagocytosed L. monocytogenes and S. aureus (5 h contact).

The differentiation of THP-1 monocytes caused: (i) a 3- to 4-fold increase in moxifloxacin uptake and a significant increase in its activity against intracellular L. monocytogenes (from 1.3 log₁₀ to 2.1 log₁₀ cfu decrease compared with the post-phagocytosis inoculum), but not against S. aureus (1.0–1.2 log₁₀ cfu decrease throughout); and (ii) no change in levofloxacin accumulation and intracellular activity against either L. monocytogenes or S. aureus.

Although differentiation of monocytes enhances the uptake and activity of moxifloxacin against L. monocytogenes, this cannot be extended to other intracellular bacteria and to levofloxacin. These results further demonstrate that antibiotic intracellular accumulation and activity are not necessarily linked and suggest that intracellular drug and pathogen combinations must be studied individually.

Antimicrobial efficacy was assessed using a carrier test method against dormant spores, germinating spores and vegetative cells of C. difficile (NCTC 11204 and ribotype 027) over a 3 h period in the presence and absence of organic matter.

Copper metal eliminated all vegetative cells of C. difficile within 30 min, compared with stainless steel which demonstrated no antimicrobial activity (P < 0.05). Copper significantly reduced the viability of spores of C. difficile exposed to the germinant (sodium taurocholate) in aerobic conditions within 60 min (P < 0.05) while achieving a ≥2.5 log reduction (99.8% reduction) at 3 h. Organic material did not reduce the antimicrobial efficacy of the copper surface (P > 0.05).

The use of copper surfaces within the clinical environment and application of a germination solution in infection control procedures may offer a novel way forward in eliminating C. difficile from contaminated surfaces and reducing CDAD.

The parasites were treated with saponins for MIC determination. Anti-Trichomonas activity of the saponins was evaluated using a cytoadherence assay, the substrate gel electrophoresis method and RT–PCR analysis. The effect of saponins on the mitochondrial potential of the host was determined by florescence-activated cell sorter. Actin cytoskeletal staining was used to determine the effect on parasite cytoskeleton.

Using in vitro susceptibility assay, the MIC of Sapindus saponins for T. vaginalis (0.005%) was found to be 10-fold lower than its effective spermicidal concentration (0.05%). Saponins concentration dependently inhibited the ability of parasites to adhere to HeLa cells and decreased proteolytic activity of the parasite’s cysteine proteinases. This was associated with decreased expression of adhesin AP65 and membrane-expressed cysteine proteinase TvCP2 genes. Saponins produced no adverse effect on host cells in mitochondrial reduction potential measurement assay. Saponins also reversed the inhibitory mechanisms exerted by Trichomonas for evading host immunity. Early response of saponins to disrupt actin cytoskeleton in comparison with their effect on the nucleus suggests a membrane-mediated mode of action rather than via induction of apoptosis.

Findings demonstrate the potential of Sapindus saponins for development as a microbicidal contraceptive for human use. Further studies are required to evaluate its microbicidal activity against other sexually transmitted infections.

In this study, a total of 98 faecal samples from slaughter pigs were tested for tetracycline and sulphonamide resistance in Escherichia coli using the single colony method, and these results were compared with the results obtained using the resistance prevalence per sample method.

The results obtained by the resistance prevalence per sample method showed a lower occurrence of resistance. Tetracycline resistance in E. coli was found in 36.7% of the samples using the single colony method, while the mean tetracycline resistance prevalence was 22.5% using the resistance prevalence per sample method. Similarly, sulphonamide resistance was 32.7% using the single colony method and 19.6% when using the resistance prevalence per sample method. Although different estimates were obtained by each method, the correlation test and the regression model demonstrated that there is a significant association between the results obtained using both methods (P value <0.01) for both antimicrobials tested.

To support risk assessment and analysis of the association between consumption of antimicrobials and occurrence of resistance, there is a need to move towards a more quantitative approach when dealing with antimicrobial resistance in a population, and the resistance prevalence per sample method can provide some of this additional information.

We used Aspergillus fumigatus (AF) 293 conidia with or without prior exposure to voriconazole or posaconazole [three serial passages on plates containing regular yeast extract-glucose (YAG) media, YAG+0.0625 mg/L voriconazole or YAG+0.025 mg/L posaconazole]. Toll-deficient Drosophila melanogaster flies were infected by injection, and 8 day survival was monitored. Following infection, flies were fed either regular food, food containing 1000 mg/L voriconazole (posaconazole-exposed conidia) or 1000 mg/L posaconazole (voriconazole-exposed conidia). Voriconazole and posaconazole concentrations in flies were confirmed by HPLC.

AF inoculation resulted in 71% mortality 8 days post-infection (median survival 4 days). Prior conidial exposure to voriconazole or posaconazole did not affect mortality (73%, P = 0.8 for voriconazole pre-exposed and 76%, P = 0.49 for posaconazole pre-exposed). Voriconazole treatment post-infection had a protective effect, reducing mortality to 42% (P = 0.0002), while prior conidial exposure to posaconazole did not alter the protective effect of voriconazole (34% 8 day mortality, P = 0.35). Likewise, posaconazole treatment post-infection reduced mortality to 36%, while prior conidial exposure to voriconazole did not alter the protective effect of posaconazole (39% mortality, P = 0.92). Median fly homogenate concentrations of voriconazole and posaconazole were 0.44 and 2.05 mg/L, respectively.

Prior exposure of AF to voriconazole or posaconazole did not affect the virulence of AF nor the subsequent activity of the alternate triazole in a Drosophila model of IA.

Immunosuppressed mice were treated with voriconazole at 60 mg/kg/day, amphotericin B at 3 mg/kg/day, micafungin at 10 mg/kg/day or combinations of these antifungal drugs. For survival studies, treatment began 1 day after infection and continued for 10 days. For tissue burden studies, animals were sacrificed on day 6 of the treatment and the fungal load in the kidneys and spleens was measured. The experiments were carried out using two different clinical strains of F. solani.

Only the combination of voriconazole plus amphotericin B prolonged the survival of the mice versus the controls for the two strains tested. However, this combination only reduced tissue burden in the kidney and spleen of mice infected by one strain. The other treatments were clearly less effective.

Voriconazole plus amphotericin B may have a role in the treatment of fusariosis.

Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824.

Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of ≤4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3–5 antitubercular drugs).

Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy.

Antisense PMO and PPMO were designed against the 5' terminal region (5'SL) or the 3'-cyclization sequence region (3'CS) of DENV genomic RNA and administered to AG129 mice before and/or after infection with DENV-2. In addition, cell culture evaluations designed to determine optimum PPMO length, and pharmacokinetic and toxicity analysis of PPMO were also carried out.

Mock-treated AG129 mice lived for 9–17 days following intraperitoneal (ip) infection with 10⁴–10⁶ pfu of DENV-2 (strain New Guinea C). Intraperitoneal administration of 5'SL or 3'CS PPMO before and after DENV infection produced an increase in the average survival time of up to 8 days. Animals receiving only post-infection PPMO treatment did not benefit significantly. Cell culture studies showed that PPMO of 22–24 bases long produced substantially higher DENV titre reductions than did PPMO that were either shorter or longer. Pharmacokinetic and toxicology analysis with non-infected animals showed that nine consecutive once-daily ip treatments of 10 mg/kg PPMO resulted in high concentrations of PPMO in the liver and caused little impact on overall health.

The data indicate that PPMO had considerable antiviral efficacy against DENV-2 in the AG129 mouse model and that PPMO treatment early in the course of an infection was critical to extending the survival times of DENV-2-infected mice in the AG129 model system.

Thirteen pigs received either intravenous (iv) or intramuscular (im) artesunate (60 mg), with the alternative preparation given 24 h later in an open crossover design. Five of them also received an additional intra-arterial (ia) artesunate dose (60 mg). The plasma concentrations of artesunate and DHA were determined by high-performance liquid chromatography with electrochemical detection. Population modelling was performed with NONMEM, using a two-compartment model.

Plasma concentration–time profiles were comparable to those observed in humans, with a rapid and biphasic decline for both artesunate and DHA. Following an iv bolus, artesunate had a median maximum plasma concentration (C_max) of 13.8 µM [interquartile range (IQR), 10.4–22.1 µM], elimination half-life (t_1/2) = 18 min (IQR, 16–22 min), total plasma clearance (CL) = 5.58 L/h/kg (IQR, 3.31–5.91 L/h/kg) and volume of distribution (V_d) = 1.85 L/kg (IQR, 1.27–3.20 L/kg). The median C_max value for DHA was 3.30 µM (IQR, 2.08–5.95 µM), t_1/2 = 26 min (IQR, 23–31 min), CL/Fm = 4.37 L/h/kg (IQR, 3.29–6.87 L/h/kg) and V_d/Fm = 2.56 L/kg (IQR, 1.93–4.49 L/kg). Artesunate and DHA pharmacokinetic parameters were similar after ia administration. Following im dosing, median artesunate C_max was 4.81 µM (IQR, 3.74–5.40 µM), t_1/2 = 18 min (IQR, 16–28 min), CL = 4.37 L/h/kg (IQR, 4.13–4.68 L/h/kg) and V_d = 2.07 L/kg (IQR, 1.83–2.79 L/kg); the bioavailability was 100%. For DHA, median C_max was 1.43 µM (IQR, 1.00–1.92 µM), t_1/2 = 27 min (IQR, 25–37 min), CL/Fm = 4.68 L/h/kg (IQR, 3.35–6.73 L/h/kg) and V_d/Fm = 3.31 L/kg (IQR, 2.89–4.27 L/kg).

The pharmacokinetic properties of artesunate and DHA in pigs were similar to those reported in humans, suggesting that the swine model is suitable for determining the preclinical pharmacokinetics of artemisinin derivatives.

In a single-centre, prospective, open-label study, nine adult cirrhosis patients were treated with 400 mg moxifloxacin infusion once a day. On days 1 and 3, drug concentrations in serum and ascites were determined before and at different time points up to 24 h after medication with a validated HPLC method.

On day 1, serum concentrations of moxifloxacin decreased from a median of 3.7 mg/L at 1 h to 0.6 mg/L at 24 h. On day 3, serum peak and trough levels were only moderately increased in comparison with day 1, with moxifloxacin concentrations of 3.9 mg/L after 1 h and 0.6 mg/L 24 h after the third infusion. The AUC values were also slightly, but not statistically significantly, increased on day 3. Calculations of t_1/2, mean residence time, CL_tot and V_ss revealed no significant differences between days 1 and 3. Median concentrations of moxifloxacin in ascitic fluid were 1.4 mg/L (3 h after infusion) and 1.3 mg/L (6 h) on day 1 and 2.1 mg/L (3 h) and 1.9 mg/L (6 h) on day 3. Median ascites/serum ratios did not vary between days 1 and 3.

PK parameters of moxifloxacin in patients with advanced liver cirrhosis differed only marginally from those from healthy control groups given in the literature. After multiple dosing, no drug accumulation was seen. Therefore, we conclude that a dose adjustment is not necessary in this patient group. Ascitic fluid reached bactericidal levels for common bacteria found in spontaneous bacterial peritonitis.

Pharmacokinetic profiles (24 h) of atazanavir/ritonavir were assessed and measured by HPLC/tandem mass spectrometry. Geometric mean (GM; ANOVA) of minimum and maximum plasma drug concentrations (C_min and C_max), area under the concentration–time curve (AUC) and total clearance (CL_total) were compared between the sexes and correlated to demographic (age, gender and ethnicity), physiological (weight and body mass index) and clinical (CD4+ cell count, HIV-RNA, co-medication and hepatitis serology) co-factors.

The GM of the atazanavir AUC, C_max and C_min of men versus women were 32 643 versus 36 232 ng·h/mL [GM ratio (GMR) = 1.11, P = 0.435], 2802 versus 3211 ng/mL (GMR = 1.15, P = 0.305) and 398 versus 470 ng/mL (GMR = 1.18, P = 0.406), respectively. Although weight (80.6 versus 63.9 kg, P = 0.001) and body weight-adjusted atazanavir dose (3.84 versus 4.60 mg/kg, P = 0.013) were different between the sexes, no significant correlation to atazanavir pharmacokinetics was observed. A linear regression analysis detected significant correlations of atazanavir C_min with ritonavir AUC (P < 0.001) and the co-administration of methadone oral solution (P = 0.032), and inverse correlations with the time since the first HIV infection diagnosis (P = 0.003) and the number of previous antiretroviral treatments (P = 0.022).

Atazanavir/ritonavir steady-state pharmacokinetics was comparable in men and women, despite gender-related significant differences in atazanavir dose/body weight. The administration of atazanavir/ritonavir is pharmacokinetically safe; 95% of all trough samples were above the recommended plasma concentration of 150 ng/mL.

We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm³ received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively.

Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non-significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely.

We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention.

The cross-sectional study included 174 GPs from 89 general practices. Data were derived from the Second Dutch National Survey of General Practice (DNSGP-2) in 2001. Outcome measures were the antibiotic prescriptions for respiratory, ear and urinary tract disorders defined according to the International Classification of Primary Care codes, the percentage of first-choice antibiotics complying with national guidelines and the number of antibiotic prescriptions per 1000 patients per GP per year.

The most antibiotics for respiratory tract infection (RTI) were prescribed for acute bronchitis (25%), sinusitis (22%) and acute upper RTI (14%). The most antibiotics were prescribed for acute otitis media (77% of ear disorders) and cystitis (95% of urinary tract disorders). First-choice antibiotics were prescribed in ~75% of the cases, whereas macrolides and amoxicillin/clavulanate (second-choice antibiotics) were prescribed in ~25%, especially in lower RTIs. The correlations (Spearman ) between prescribed volumes for the three main groups of disorders varied from 0.39 to 0.67.

GPs were consistent in prescribing antibiotics for the three groups of diseases. Improvement strategies should focus on the management of acute upper RTIs and acute bronchitis and also on the use of amoxicillin/clavulanate and macrolides, these being mostly second-choice antibiotics in national guidelines.

The present research involved the retrospective collection of monthly data on the usage of antibiotics and on infection control practices within the hospital over a 5 year period (January 2000–December 2004). A multivariate ARIMA (time-series analysis) model was built to relate MRSA incidence with antibiotic use and infection control practices.

Analysis of the 5 year data set showed that temporal variations in MRSA incidence followed temporal variations in the use of fluoroquinolones, third-generation cephalosporins, macrolides and amoxicillin/clavulanic acid (coefficients = 0.005, 0.03, 0.002 and 0.003, respectively, with various time lags). Temporal relationships were also observed between MRSA incidence and infection control practices, i.e. the number of patients actively screened for MRSA (coefficient = –0.007), the use of alcohol-impregnated wipes (coefficient = –0.0003) and the bulk orders of alcohol-based handrub (coefficients = –0.04 and –0.08), with increased infection control activity being associated with decreased MRSA incidence, and between MRSA incidence and the number of new patients admitted with MRSA (coefficient = 0.22). The model explained 78.4% of the variance in the monthly incidence of MRSA.

The results of this study confirm the value of infection control policies as well as suggest the usefulness of restricting the use of certain antimicrobial classes to control MRSA.

An interventional time-series analysis was performed to evaluate the impact of two promotion campaigns on the consumption of ABHRs and to assess their effect on the incidence of non-duplicate clinical isolates of MRSA and C. difficile from February 2000 through September 2006. This analysis was combined with a transfer function model of aggregated data on antibiotic use.

Consumption of ABHRs correlated with MRSA, but not with C. difficile. The final model demonstrated the immediate effect of the second hand hygiene promotion campaign and an additional temporal effect of fluoroquinolone (time lag, 1 month; i.e. antibiotic effect delayed for 1 month), macrolide (lag 1 and 4 months), broad-spectrum cephalosporins (lag 3, 4 and 5 months) and piperacillin/tazobactam (lag 3 months) use. The final model explained 57% of the MRSA variance over time. In contrast, the model for C. difficile showed only an effect for broad-spectrum cephalosporins (lag 1 month).

We observed an aggregate-level relation between the monthly MRSA incidence and the use of different antibiotic classes and increased consumption of ABHR after a successful hand hygiene campaign, while no association with ABHR use was detected for C. difficile.

The study was conducted at a tertiary referral teaching hospital in Melbourne, Australia. The system was deployed in January 2005 and guided the use of 28 restricted antimicrobials. Data were collected over 7 years: 5 years before and 2 years after deployment. Uptake of the system was evaluated using an in-built audit trail. Drug utilization was prospectively monitored using pharmacy data (as defined daily doses per 1000 bed-days) and analysed via time-series analysis with segmental linear regression. Antibiograms of local bacteria were prospectively evaluated. In-hospital mortality and length of stay for patients with Gram-negative bacteraemia were also reported.

Between 250 and 300 approvals were registered per month during 2006. The gradients in the use of third- and fourth-generation cephalosporins (+0.52, –0.05, –0.39; P < 0.01), glycopeptides (+0.27, –0.53; P = 0.09), carbapenems (+0.12, –0.24; P = 0.21), aminoglycosides (+0.15, –0.27; P < 0.01) and quinolones (+0.76, +0.11; P = 0.08) all fell after deployment, while extended-spectrum penicillin use increased. Trends in increased susceptibility of Staphylococcus aureus to methicillin and improved susceptibility of Pseudomonas spp. to many antibiotics were observed. No increase in adverse outcomes for patients with Gram-negative bacteraemia was observed.

The system was successfully adopted and significant changes in antimicrobial usage were demonstrated.

Registers of all approved antimicrobial commercial products, kept by the French Agency for Veterinary Medicinal Products (AFSSA ANMV) for animals and the French Health Products Safety Agency (AFSSAPS) for humans, were compared to determine whether the same antimicrobials were approved in 2007 for use in both human and animal populations. Sales data were collected from pharmaceutical companies between 1999 and 2005 by the AFSSA ANMV and AFSSAPS. Usage of the different antimicrobial anatomical therapeutic chemical (ATC) classes in human and veterinary medicines was recorded. Data were expressed in tonnes of active ingredients and were then related to the animal and human biomasses to compare usages expressed in mg/kg.

All antimicrobial ATC classes were used in both human and veterinary medicine. Tetracyclines accounted for the most sales in veterinary medicine. β-Lactams predominated in human medicine. A decrease in the amounts consumed by both human and animal populations was observed during the study. In 2005, 760 tonnes were used in human medicine and 1320 tonnes in veterinary medicine, corresponding to 199 and 84 mg/kg of live weight in human and animal populations, respectively.

The same antimicrobial drugs were used in human and veterinary medicines but the quantitative patterns of use were different. Expression of antimicrobial usage is a key point to address when comparing usage trends.