International Journal of Antimicrobial Agents - Articles in Press

Activity of JNJ-Q2, a new fluoroquinolone, tested against contemporary pathogens isolated from patients with community-acquired bacterial pneumonia - Corrected Proof

2012-02-06

Abstract: JNJ-Q2 is a broad-spectrum fluoroquinolone with bactericidal activity against Gram-positive and Gram-negative pathogens and is currently in clinical development for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin-structure infections. This study determined the activity of JNJ-Q2 against a worldwide year 2010 collection (89 centres in 27 countries) of three common respiratory pathogens (3757 isolates) from patients with CABP. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were tested by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, and susceptibility rates for comparators were assessed using CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria. JNJ-Q2 had activity against all three species, with 96.9% of strains inhibited at ≤0.015mg/L. JNJ-Q2 [minimum inhibitory concentration for 50% and 90% of the organisms, respectively (MIC50/90)=0.008/0.015mg/L] demonstrated a 16-fold greater potency compared with moxifloxacin (MIC50/90=0.12/0.25mg/L) and at least 128-fold greater activity compared with levofloxacin (MIC50/90=1/1mg/L) and ciprofloxacin (MIC50/90=1/2mg/L) against S. pneumoniae. Haemophilus influenzae isolates were 21.9–23.3% resistant to ampicillin, but JNJ-Q2 (MIC50/90≤0.004/0.015mg/L) was at least two-fold more active than moxifloxacin (MIC50/90=0.015/0.03mg/L) as well as being potent against M. catarrhalis (MIC90=0.015/0.015mg/L). In conclusion, JNJ-Q2 demonstrated increased potency compared with other marketed fluoroquinolones that have been used to treat CABP pathogens, thus favouring further clinical development.

Commentary on: Does empirical treatment of community-acquired pneumonia with fluoroquinolones delay tuberculosis treatment and result in fluoroquinolone resistance in Mycobacterium tuberculosis? Controversies and solutions - Corrected Proof

Gabriel Levy Hara — 2012-02-03

The review in this journal by Shen et al. addresses one of the current controversies regarding antimicrobial therapy: which drug should be selected for the initial treatment of community-acquired pneumonia (CAP), both in ambulatory and hospital settings?

Does empirical treatment of community-acquired pneumonia with fluoroquinolones delay tuberculosis treatment and result in fluoroquinolone resistance in Mycobacterium tuberculosis? Controversies and solutions - Corrected Proof

2012-01-27

Abstract: The role of fluoroquinolones (FQs) as empirical therapy for community-acquired pneumonia (CAP) remains controversial in countries with high tuberculosis (TB) endemicity owing to the possibility of delayed TB diagnosis and treatment and the emergence of FQ resistance in Mycobacterium tuberculosis. Although the rates of macrolide-resistant Streptococcus pneumoniae and amoxicillin/clavulanic acid-resistant Haemophilus influenzae have risen to alarming levels, the rates of respiratory FQ (RFQ) resistance amongst these isolates remain relatively low. It is reported that ca. 1–7% of CAP cases are re-diagnosed as pulmonary TB in Asian countries. A longer duration (≥7 days) of symptoms, a history of night sweats, lack of fever (>38°C), infection involving the upper lobe, presence of cavitary infiltrates, opacity in the lower lung without the presence of air, low total white blood cell count and the presence of lymphopenia are predictive of pulmonary TB. Amongst patients with CAP who reside in TB-endemic countries who are suspected of having TB, imaging studies as well as aggressive microbiological investigations need to be performed early on. Previous exposure to a FQ for >10 days in patients with TB is associated with the emergence of FQ-resistant M. tuberculosis isolates. However, rates of M. tuberculosis isolates with FQ resistance are significantly higher amongst multidrug-resistant M. tuberculosis isolates than amongst susceptible isolates. Consequently, in Taiwan and also in other countries with TB endemicity, a short-course (5-day) regimen of a RFQ is still recommended for empirical therapy for CAP patients if the patient is at low risk for TB.

Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities - Corrected Proof

Francesco Scaglione, Liberato Berrino — 2012-01-24

Abstract: The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure–activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2′,3′-dideoxycytidine (ddC; zalcitabine), 2′,3′-dideoxy-3′-thiacytidine (3TC; lamivudine) and 2′,3′-dideoxy-5-fluoro-3′-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.

Antimicrobial susceptibility of Streptococcus pneumoniae isolates from vaccinated and non-vaccinated patients with a clinically confirmed diagnosis of community-acquired pneumonia in Belgium - Corrected Proof

2012-01-16

Abstract: We assessed the in vitro susceptibility of Streptococcus pneumoniae isolates from patients with confirmed community-acquired pneumonia (CAP) to β-lactams, macrolides and fluoroquinolones and the association of non-susceptibility and resistance with serotypes/serogroups (STs/SGs), patient's risk factors and vaccination status. Samples (blood or lower respiratory tract) were obtained in 2007–2009 from 249 patients (from seven hospitals in Belgium) with a clinical and radiological diagnosis of CAP [median age 61 years (11.6% aged <5 years); 85% without previous antibiotic therapy; 86% adults with level II Niederman's severity score]. MIC determination (EUCAST breakpoints) showed for: (i) amoxicillin, 6% non-susceptible; cefuroxime (oral), 6.8% resistant; (ii) macrolides: 24.9% erythromycin-resistant [93.5% erm(B)-positive] but 98.4% telithromycin-susceptible; and (iii) levofloxacin and moxifloxacin, all susceptible. Amongst SGs: ST14, all resistant to macrolides and most intermediate to β-lactams; SG19 (>94% ST19A), 73.5% resistant to macrolides and 18–21% intermediate to β-lactams; and SG6, 33% resistant to clarithromycin. Apparent vaccine failures: 3/17 for 7-valent vaccine (children; ST6B, 23F); 16/29 for 23-valent vaccine (adults ST3, 7F, 12F, 14, 19A, 22F, 23F, 33F). Isolates from nursing home residents, hospitalised patients and patients with non-respiratory co-morbidities showed increased MICs for amoxicillin, all β-lactams, and β-lactams and macrolides, respectively. Regarding antibiotic susceptibilities: (i) amoxicillin is still useful for empirical therapy but with a high daily dose; (ii) cefuroxime axetil and macrolides (but not telithromycin) are inappropriate for empirical therapy; and (iii) moxifloxacin and levofloxacin are the next ‘best empirical choice’ (no resistant isolates) but levofloxacin will require 500mg twice-daily dosing for effective coverage.

Efficacy and mechanism of action of arachidonic acid in the treatment of hamsters infected with Schistosoma mansoni or Schistosoma haematobium - Corrected Proof

2012-01-13

Abstract: We have recently shown that in vitro and in vivo exposure of Schistosoma mansoni and Schistosoma haematobium to 5–10mM arachidonic acid (ARA) induces parasite surface membrane disintegration and eventual attrition. Here we report on the optimum ARA dose and post-infection treatment time for maximum schistosome demise in hamsters. A series of four experiments for each schistosome species indicated that oral administration of ARA after patency led to a highly significant (P<0.02 to <0.001) reduction in worm burden accompanied by a significant (P<0.05) decrease in worm egg load. ARA-mediated attrition in vivo appeared to be associated with high titres of serum antibodies to tegumental antigens. In support, serum antibodies from patently infected and ARA-treated hamsters readily bound to the surface membrane of ARA-exposed adult worms, as judged by indirect membrane immunofluorescence. More importantly, addition of serum antibodies and peripheral blood mononuclear cells significantly enhanced ARA-mediated adult worm attrition in vitro. These data together show that the schistosomicidal effect of ARA in laboratory animals is enhanced by immune effectors and is highly efficacious and entirely safe.

Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin - Corrected Proof

Anucha Apisarnthanarak, Linda M. Mundy — 2012-01-11

Alternative treatment strategies are needed to optimise the efficacy of treatment for infections due to multidrug-resistant pathogens . Pharmacokinetic and pharmacodynamic data for carbapenems, in conjunction with findings from a recent observational study, suggest a benefit of high-dose, 4-h infusion of doripenem in combination with fosfomycin for the treatment of carbapenem-resistant Pseudomonas aeruginosa (CRPA) with minimum inhibitory concentrations (MICs) of 4–8mg/L for doripenem . We conducted a study to compare high-dose, 4-h infusion of doripenem in combination with fosfomycin versus intravenous (i.v.) colistin in combination with fosfomycin for the treatment of CRPA with MICs of 4–8mg/L for doripenem.

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation - Corrected Proof

2012-01-10

Abstract: Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone±linezolid (comparator group). Clinical and microbiological outcomes were determined 7–14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, −6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, −9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, −12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone±linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrails.gov identifier: NCT00326287]

Intracellular concentrations of micafungin in different cellular compartments of the peripheral blood - Corrected Proof

2012-01-10

Abstract: Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n=26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P<0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations.

How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics - Corrected Proof

2012-01-09

Abstract: Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate individualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available.

Efficacy of intrathecal administration of liposomal amphotericin B combined with voriconazole in a murine model of cryptococcal meningitis - Corrected Proof

Alexandra F. Gazzoni, Javier Capilla, Emilio Mayayo, Josep Guarro — 2012-01-09

Abstract: Meningitis is one of the most fatal manifestations of cryptococcosis, even with specific treatment. Combination of a prompt diagnosis and appropriate therapy are critical to reduce the fungal load and the inflammatory response effects of the proliferation of yeast into the central nervous system (CNS). Mice with experimental acute meningitis caused by Cryptococcus neoformans were treated with liposomal amphotericin B (L-AmB) administered intrathecally (i.t.c.) at 0.006mg/kg weekly or intravenously (i.v.) at 10mg/kg daily or with voriconazole (VCZ) administered orally at 30mg/kg per dose twice daily or with combinations of both drugs, i.e. L-AmB i.t.c.+VCZ or L-AmB i.v.+VCZ at the same doses as used in the monotherapies. All treatments significantly increased the survival of animals in comparison with the control group, with VCZ being less effective in comparison with all other treatments (P≤0.012). All treatments, with the exception of VCZ (P=0.533), reduced fungal burdens in the brain in comparison with controls. The combination of L-AmB i.t.c.+VCZ showed a synergistic effect in the reduction of fungal load that was significantly superior to any tested therapy (P≤0.039). Histologically, untreated animals showed a marked inflammatory response with massive fungal cells in the meninges, whilst treated animals showed a variable number of fungal cells in the CNS, with the exception of animals receiving L-AmB i.t.c.+VCZ in which neither yeasts nor inflammation were observed.

Emergence of Escherichia coli sequence type 410 (ST410) with KPC-2 β-lactamase - Corrected Proof

2012-01-09

Abstract: Fifteen carbapenem-non-susceptible Escherichia coli isolates obtained during the period May 2010 to April 2011 in a hospital and a long-term care facility (LTCF) in Larissa (Central Greece) were investigated. Minimum inhibitory concentrations (MICs) to various antimicrobial agents were determined by Etest. Carriage of bla genes, including blaKPC-2 and blaCTX-M, was documented by polymerase chain reaction (PCR) and sequencing. Production of β-lactamases was confirmed by isoelectric focusing. Transfer of resistance was carried out by conjugation. Plasmid incompatibility groups were determined by PCR-based replicon typing and replicon sequence typing. Isolates were genotyped by multilocus sequence typing. Ten E. coli isolates with KPC-2 were derived from seven patients in the University Hospital of Larissa. Six patients had previously been treated for prolonged time periods in a LTCF located in the same city. The remaining isolate was from a patient previously treated in an Athens hospital. Screening of faecal samples from 20 randomly selected LTCF patients yielded eight enterobacteria with KPC-2, of which five were E. coli, showing the wide spread of KPC-2-producers in this institution and confirming that it was the focus of the outbreak. Fourteen of the isolates were classified as sequence type 410 (ST410); the remaining isolate belonged to a novel ST (ST2281). All 15 isolates carried a KPC-2-encoding plasmid of the Inc group FIIK. Additional plasmids encoding enzymes of the CTX-M-1 family were identified in 11 isolates. The blaKPC-2-carrying plasmid IncFIIK, widespread amongst Klebsiella pneumoniae in Greece, has probably been acquired by E. coli ST410 known to be associated with CTX-M production. Diffusion of blaKPC-2 in common pathogens such as E. coli is of concern.

Molecular characterisation of high-level gentamicin-resistant enterococci from bloodstream infections in Denmark: first description of clonal spread of aph(2′′)-Ib - Corrected Proof

2012-01-09

Enterococcal bloodstream infections (BSIs) are emerging in Danish hospitals . In the present study, high-level gentamicin-resistant (HLGR) Enterococcus faecalis and HLGR Enterococcus faecium isolates from BSIs in patients from Danish hospitals were characterised.

Efficacy of miltefosine treatment in Leishmania amazonensis-infected BALB/c mice - Corrected Proof

2012-01-09

Abstract: Leishmaniasis is one of the most serious worldwide diseases caused by protozoan parasites of the Leishmania genus, affecting millions of people around the world. All currently available treatments present severe toxic side effects, require long-term compliance, cause serious side effects and are uncomfortable for patients. Leishmania amazonensis, a species endemic to Brazil, causes severe localised or diffuse skin lesions in humans. Owing to the unsatisfactory nature of the currently available chemotherapies, new approaches have been assessed for improved therapeutic intervention strategies against leishmaniasis. Miltefosine is an alkylphospholipid analogue that exhibits potent activity against the different clinical manifestations of leishmaniasis. Thus, the aim of this study was to investigate the long-term efficacy of miltefosine in BALB/c mice infected with L. amazonensis owing to the lack of a profound study demonstrating its dose-dependent and long-term effects. It was observed that animals treated with 20–50mg/kg/day of miltefosine exhibited a significant dose-dependent reduction in lesion size; furthermore, in mice receiving higher doses, lesions disappeared after the end of treatment. To confirm a possible parasitological cure, mice up to 250 days after the end of treatment were analysed. No lesions or presence of parasite DNA were found in mice treated with 30, 40 and 50mg/kg/day of miltefosine. In summary, these results show that miltefosine may be used to treat cutaneous leishmaniasis caused by L. amazonensis, alone or as combination therapy.

Update on the prevention and control of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) - Corrected Proof

2012-01-09

Abstract: The rapid dissemination of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) since the early 2000s and the appearance of new successful lineages is a matter of concern. The burden of these infections varies widely between different groups of individuals and in different regions of the world. Estimating the total burden of disease is therefore problematic. Skin and soft-tissue infections, often in otherwise healthy young individuals, are the most common clinical manifestation of these infections. The antibiotic susceptibilities of these strains also vary, although they are often more susceptible to ‘traditional’ antibiotics than related hospital-acquired strains. Preventing the dissemination of these organisms throughout the general population requires a multifaceted approach, including screening and decolonisation, general hygiene and cleaning measures, antibiotic stewardship programmes and, in the future, vaccination. The current evidence on the prevention and control of CA-MRSA is appraised and summarised in this review.

Mechanism of resistance of a highly carbapenem-resistant Klebsiella oxytoca isolate and comparison of susceptibility to five carbapenems - Corrected Proof

2012-01-09

Klebsiella oxytoca is an important opportunistic pathogen that causes septicaemia, pneumonia and urinary tract infections in hospitalised patients, including neonates. Whilst most Klebsiella spp., including K. oxytoca, have long been susceptible to carbapenems, Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant K. pneumoniae strains were first reported in 2001 in North Carolina (USA) . Since 2001, KPC has become the most prevalent mechanism of carbapenem resistance in K. pneumoniae, and KPC-producing K. pneumoniae has been reported in the USA, Israel, Turkey, China, India, the UK and Nordic countries . Another carbapenemase-producing, carbapenem-resistant K. pneumoniae harbouring New Delhi metallo-β-lactamase (NDM-1) was isolated from a Swedish patient at a hospital in India in 2009 , which became a worldwide concern because of potential dissemination to other countries. Fortunately, KPC- and NDM-1-producing K. pneumoniae are still uncommon in Japan. The most clinically important carbapenemases in Japan are the metallo-β-lactamases (MBLs) IMP-1 and VIM-2, as they have already been disseminated into several members of the Enterobacteriaceae family, including K. pneumoniae and K. oxytoca .

Purified 1′acetoxychavicol acetate (1′ACA) from galangal spice affects membrane fatty acid composition and triggers a cell envelope stress response in Staphylococcus aureus - Corrected Proof

2012-01-09

Staphylococcus aureus is a significant cause of community- and hospital-acquired infections worldwide. New effective control measures for S. aureus are needed and natural antimicrobial compounds from edible plants represent one novel source. The rhizome of galangal (Alpinia galanga) is widely used as a spice for food flavouring and in traditional medicine and has strong antimicrobial activity against S. aureus. In this study, we provide insight into the mechanism of action and subcellular target of the major galangal extract compound, 1′acetoxychavicol acetate (1′ACA), in meticillin-resistant S. aureus (MRSA) ATCC 49476. Changes in cell morphology, membrane fatty acid composition and levels of stress response gene expression in response to purified 1′ACA were examined.

Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods - Corrected Proof

2012-01-09

Abstract: This article reviews recent findings on the global epidemiology of healthcare-acquired/associated (HA), community-acquired/associated (CA) and livestock-associated (LA) meticillin-resistant Staphylococcus aureus (MRSA) and aims to reach a consensus regarding the harmonisation of typing methods for MRSA. MRSA rates continue to increase rapidly in many regions and there is a dynamic spread of strains across the globe. HA-MRSA is currently endemic in hospitals in most regions. CA-MRSA clones have been spreading rapidly in the community and also infiltrating healthcare in many regions worldwide. To date, LA-MRSA is only prevalent in certain high-risk groups of workers in direct contact with live animals. CA-MRSA and LA-MRSA have become a challenge for countries that have so far maintained low rates of MRSA. These evolutionary changes have resulted in MRSA continuing to be a major threat to public health. Continuous efforts to understand the changing epidemiology of S. aureus infection in humans and animals are therefore necessary, not only for appropriate antimicrobial treatment and effective infection control but also to monitor the evolution of the species. The group made several consensus decisions with regard to harmonisation of typing methods. A stratified, three-level organisation of testing laboratories was proposed: local; regional; and national. The functions of, and testing methodology used by, each laboratory were defined. The group consensus was to recommend spa and staphylococcal cassette chromosome mec (SCCmec) typing as the preferred methods. Both are informative in defining particular strain characteristics and utilise standardised nomenclatures, making them applicable globally. Effective communication between each of the different levels and between national centres was viewed as being crucial to inform and monitor the molecular epidemiology of MRSA at national and international levels.

Comparative Activity of Carbapenem Testing (COMPACT) study in Germany - Corrected Proof

2012-01-09

Abstract: The aim of this study was to determine the current susceptibility of hospital isolates of contemporary Gram-negative pathogens to the carbapenems doripenem, imipenem and meropenem. Between May and October 2008, seven centres in Germany were invited to collect and submit Pseudomonas aeruginosa, Enterobacteriaceae and other Gram-negative bacterial Intensive Care Unit (ICU)/non-ICU isolates from patients with complicated intra-abdominal infections (cIAIs), bloodstream infections (BSIs) or nosocomial pneumonia (NP). Susceptibility was determined at each centre by Etest. A central laboratory performed species confirmation as well as limited susceptibility and quality control testing. In total, 363 isolates were collected, comprising 46.0% Enterobacteriaceae, 45.2% P. aeruginosa, 4.7% Acinetobacter spp. and 4.1% other Gram-negatives. Most isolates (47.9%) were collected from NP, 32.8% were from cIAIs and 19.3% from BSIs; 57.3% were obtained from ICU patients. The MIC90 values (minimum inhibitory concentration for 90% of the isolates) for doripenem, meropenem and imipenem were, respectively, 4, 16 and 32mg/L against P. aeruginosa, 0.06, 0.06 and 0.5mg/L against Enterobacteriaceae and ≥64mg/L for each carbapenem against other Gram-negative isolates. Using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 81.1%, 75.6% and 79.3% of P. aeruginosa were susceptible to doripenem, imipenem and meropenem, respectively. Against all pathogens combined, MIC90 values for ICU versus non-ICU isolates, respectively, were 4mg/L vs. 1mg/L for doripenem, 8mg/L vs. 1mg/L for meropenem and ≥64mg/L vs. 8mg/L for imipenem. Doripenem showed comparable activity against P. aeruginosa from patients with BSIs, cIAIs or NP. Similar findings were observed for Enterobacteriaceae and other Gram-negatives, including Acinetobacter spp. Doripenem generally showed similar or slightly better activity than meropenem and better activity than imipenem against Gram-negative pathogens collected in Germany.

Efficacies of colistin and tigecycline in mice with experimental pneumonia due to NDM-1-producing strains of Klebsiella pneumoniae and Escherichia coli - Corrected Proof

2011-12-09

Abstract: New Delhi metallo-β-lactamase-1 (NDM-1)-producing Enterobacteriaceae have emerged as a global threat. The aim of this study was to assess the efficacies of colistin and tigecycline in an experimental model of pneumonia caused by NDM-1-producing Escherichia coli and Klebsiella pneumoniae. The susceptibilities of K. pneumoniae NDM, E. coli NDM and K. pneumoniae ATCC 29665 were determined using the broth microdilution technique. The pharmacokinetics of colistin and tigecycline in an experimental model of pneumonia were performed using immunocompetent C57BL/6 mice. Mice were treated with colistin (60mg/kg/day) or tigecycline (10mg/kg/day). Mortality, bacteraemia and lung bacterial concentrations were recorded. The strains were susceptible to colistin and tigecycline. The ratio of area under the concentration–time curve/minimum inhibitory concentration (AUC/MIC) for colistin was 158.5 (all three strains) and that for tigecycline was 18.5 (K. pneumoniae NDM) and 37 (K. pneumoniae ATCC 29665 and E. coli NDM). In vivo, colistin decreased bacterial lung concentrations of K. pneumoniae NDM and K. pneumoniae ATCC 29665 by 1.16log colony-forming units (CFU)/g and 2.23logCFU/g, respectively, compared with controls (not significant). Tigecycline reduced K. pneumoniae NDM and K. pneumoniae ATCC 29665 load by 2.67logCFU/g and 4.62logCFU/g (P<0.05). Colistin and tigecycline decreased lung concentrations of E. coli NDM by 2.27logCFU/g and 4.15logCFU/g (P<0.05), respectively, compared with controls, and was more active than colistin (P<0.05). In conclusion, these results suggest that colistin is inappropriate for treating pneumonia due to NDM-1-producing K. pneumoniae and its efficacy was suboptimal against NDM-1-producing E. coli. A high tigecycline dose was efficacious for treating experimental pneumonia due to NDM-1-producing E. coli and K. pneumoniae.

Prevalence of New Delhi metallo-β-lactamase (NDM-1)-positive bacteria in a tertiary care centre in Pune, India - Corrected Proof

2011-12-05

Metallo-β-lactamases (MBLs) are molecularly diverse carbapenemases that are emerging as a global health threat to mankind. The latest addition to the armamentarium of MBLs is the New Delhi MBL (NDM-1), a novel MBL encoded by the blaNDM-1 gene. This new MBL is reported to have arisen from the Indian subcontinent and to have spread globally thereafter . Since data regarding the prevalence of blaNDM-1-carrying isolates in hospitals in India is scant, an attempt was made to assess the prevalence of these isolates in a tertiary care centre in Western India.

Optimising amikacin regimens in septic patients - Corrected Proof

Fabio Silvio Taccone — 2011-11-28

I read with interest the article by Gálvez et al. dealing with amikacin regimens to administer in septic patients. The authors confirmed our data from a previously published study in which higher than recommended amikacin dosages (25mg/kg) were necessary to achieve optimal peak drug concentrations (Cmax) in this population. Moreover, they also suggested that this strategy was not associated with the occurrence of renal toxicity due to aminoglycosides. Although antibiotic dose adjustments in critically ill patients are often necessary to optimise their antimicrobial activity, some findings of this study need to be discussed further. First, the authors stated that amikacin regimens should target peaks >60μg/mL in most patients. However, this is true only for Pseudomonas aeruginosa or other strains with minimal inhibitory concentrations (MICs) of 8μg/mL, as the Cmax/MIC ratio that maximises aminoglycosides activity should be ≥8 . Even if these problematic bacteria should be considered when empirical antibiotic therapy is initiated for severe nosocomial infections, for more sensitive pathogens lower peak concentrations should be achieved and amikacin regimens rapidly adjusted to a different daily dose. Moreover, one may argue that the impact of aminoglycoside therapy for these susceptible strains would be more limited than in Pseudomonas infections.

Effect of vinyl sulfone inhibitors of cysteine proteinases on Tritrichomonas foetus infection - Corrected Proof

Eduardo R. Cobo, Sharon L. Reed, Lynette B. Corbeil — 2011-11-21

Abstract: Tritrichomonas foetus is a sexually transmitted protozoon that causes genital inflammation and adverse pregnancy outcomes in cattle. Cysteine proteinases (CPs) released by T. foetus degrade immunoglobulin G (IgG) antibodies, complement component 3 and matrix proteins as well as inducing apoptosis of bovine genital epithelial cells. In this study, the efficacies of the vinyl sulfone CP inhibitors K11777 and WRR-483 were tested against CPs of T. foetus. The activity of secreted T. foetus CPs in culture supernatants was decreased in the presence of vinyl sulfone inhibitors. Inhibitor K11777 reduced the in vitro cytopathogenic effects of T. foetus in bovine foetal trophoblast cells, which are relevant target cells since this pathogen interferes with pregnancy. Pre-treatment of T. foetus prior to intravaginal inoculation diminished genital infection in a murine model. Therefore, vinyl sulfone CP inhibitors reduce several effects of T. foetus-secreted CPs, including cytotoxicity on relevant target host cells and genital infection in a murine model. These inhibitors have potential as chemotherapeutic agents against bovine trichomoniasis. Generalisation to human trichomoniasis requires further study.

Molecular characterisation of high-level ciprofloxacin-resistant Salmonella enterica with multiple antibiotic resistance and class 1 integrons isolated from imported foods - Corrected Proof

Tatsuya Akiyama, Ashraf A. Khan, M.S. Nawaz, Christine S. West — 2011-11-21

Dissemination of antibiotic resistance amongst pathogenic bacteria has been a concern for public health since commercialisation of antimicrobial drugs. This includes (i) spread of antibiotic resistance determinants associated with mobile genetic elements, (ii) increase of antibiotic-resistant populations, including those carrying mutations, in the presence of selective pressure and (iii) dissemination of antibiotic-resistant bacteria that can be donors of resistance determinants as well as dominate the population under selective pressure. Recent spread of a new metallo-β-lactamase gene, blaNDM-1, from East Asian countries to the USA, UK and Australia has strengthened the need for tracking antibiotic resistance internationally to prevent further dissemination of resistance .

Interplay between mutational and horizontally acquired resistance mechanisms and its association with carbapenem resistance amongst extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) - Corrected Proof

2011-11-14

Abstract: Between 2003 and 2009, the prevalence of extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) increased significantly in northern Taiwan from 1.0% to 2.1%. Molecular methods were used to investigate the genetic relatedness and carbapenem resistance mechanisms of a collection of 203 non-repetitive XDR-PA isolates available for study. Using pulsed-field gel electrophoresis (PFGE), 52 genotypes were observed; one predominant genotype (pulsotype 1) was found in 57.6% of the isolates. Polymerase chain reaction (PCR), sequencing and quantitative reverse-transcriptase PCR analyses demonstrated that one horizontally acquired mechanism [metallo-β-lactamase (MBL) genes] and two mutational mechanisms (efflux and porins) accounted for the carbapenem resistance. The most predominant horizontally acquired mechanism was carriage of blaVIM-3, which was found in 61.1% of isolates. Decreased expression of oprD was the most prevalent mutational mechanism and was found in 70.0% of the XDR-PA isolates, whereas overexpression of mexA was found in 27.6% of the isolates. The highlight of this study was the discovery of statistically significant relationships between certain horizontally acquired and mutational resistance mechanisms and their contribution to carbapenem susceptibility. MBL-producers expressed significantly lower MexAB and higher OprD than non-MBL-producers. Amongst isolates without an acquired β-lactamase gene, oprD expression was significantly reduced, whilst expression of efflux pumps was increased. Reduced OprD expression alone or the production of VIM-type MBLs showed similar contributions to a low to intermediate MIC50 (minimum inhibitory concentration for 50% of the organisms) for carbapenems. Isolates with reduced OprD expression that simultaneously harboured blaVIM exhibited high levels of resistance to carbapenems, which implied that these two mechanisms had a synergistic effect on the MICs.

WITHDRAWN: Synergistic interaction of aciclovir and a helicase-primase inhibitor, BAY 57-1293, against herpes simplex virus type 1 - Corrected Proof

Manish Kumar, Hilary W. Thompson, Emily D. Varnell, Herbert E. Kaufman — 2009-01-27

This article has been withdrawn at the request of the author(s). The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: High frequency of mutations in the rpoB gene in rifampicin-resistant clinical isolates of Mycobacterium tuberculosis from Iran - Corrected Proof

Farahnoosh Doustdar, Azar Dokht Khosravi, Parissa Farnia, Ahmad Reza Bahremand — 2007-10-16

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.