International Journal of Antimicrobial Agents - Articles in Press

Intrinsic fluoroquinolone resistance in Orientia tsutsugamushi - Corrected Proof

2010-02-08

Abstract: Scrub typhus is a public health concern for a population of over a billion humans, with an estimated incidence of one million cases/year in endemic areas. Although doxycycline remains the standard therapy, fluoroquinolones have been used successfully in a few patients. However, there is also clinical evidence that fluoroquinolones are ineffective in the treatment of scrub typhus. To clarify this matter, we determined the in vitro susceptibility of Orientia tsutsugamushi strain Kato to ciprofloxacin and ofloxacin and sequenced the quinolone resistance-determining region (QRDR) of the gyrA gene, the target of fluoroquinolones, of 18 fresh isolates from the Lao PDR. Orientia tsutsugamushi strain Kato was resistant to ciprofloxacin and ofloxacin in vitro (minimum inhibitory concentration=8μg/mL). All sequences obtained, including those from the two available genomes of O. tsutsugamushi (strains Boryong and Ikeda), had a Ser83Leu mutation in their QRDR domain that is known to be associated with fluoroquinolone resistance. These findings re-emphasise the usefulness of in silico analysis for the prediction of antibiotic resistance and suggest that fluoroquinolones should not be used in the treatment of scrub typhus.

CTX-M-35 extended-spectrum β-lactamase conferring ceftazidime resistance in Citrobacter koseri - Corrected Proof

2010-02-08

CTX-M-type extended-spectrum β-lactamases (ESBLs) are a group of ESBLs that are becoming increasingly common worldwide. Over 90 CTX-M-type enzymes have been registered (http://www.lahey.org/studies), belonging to five clusters based on amino acid sequence homology. Unlike TEM- and SHV-type ESBLs, most CTX-M-type ESBLs have strong substrate preference for cefotaxime over ceftazidime. Here we report identification of a CTX-M-2 variant that preferentially hydrolyses ceftazidime, obtained from a clinical isolate in the USA.

Geographic distribution of fluoroquinolone-resistant Escherichia coli strains in Asia - Corrected Proof

2010-02-08

Abstract: Fluoroquinolone (FQ) resistance is usually caused by point mutations within the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and/or parE. However, little is known about the worldwide increase in FQ-resistant Escherichia coli or, more specifically, about the geographical distribution of QRDR mutations and the clonal spread of isolates. In this study, we analysed 68 FQ-resistant E. coli isolates from eight Asian countries using QRDR amino acid mutation patterns and examined their susceptibility to FQs. Of the isolates, 38% had mutations at S83 and D87 of GyrA and S80 of ParC (MM/−/M−/−) and 34% had mutations at S83 and D87 of GyrA, S80 of ParC and S458 of ParE (MM/−/M−/M). MIC50 values (minimum inhibitory concentrations for 50% of the isolates) for isolates with at least mutation at S458 of ParE for ciprofloxacin and prulifloxacin were relatively higher than MIC50 values of isolates without this mutation. Based on their geographic distribution and the QRDR mutation patterns, the isolates were divided into a common type in which the organisms were isolated from three or more countries, and a local type in which the isolates were from one or two countries. Mutation types at S83L and D87N in GyrA and S80I in ParC with no or another site in the QRDR were the most frequent among the FQ-resistant isolates, especially among the common type. Gene typing indicated that isolates in the common type were not similar between countries. These data suggest that the increase in FQ-resistant E. coli strains is mainly generated by mutations in the QRDR in each geographical area rather than through intercontinental spread.

Complete nucleotide sequence of the fosfomycin resistance transposon Tn2921 - Corrected Proof

Asunción Seoane, Felix J. Sangari, Juan M. García Lobo — 2010-02-08

Fosfomycin is a cell wall-active antibiotic introduced into clinical practice around 1970 . Despite its broad spectrum of activity and good pharmacological properties, its use has been somewhat hampered by the high number of spontaneous resistant mutants isolated following antibiotic challenge in many bacterial pathogens , most of them carrying chromosomal mutations impairing drug transport.

Susceptibility to five antifungals of Aspergillus fumigatus strains isolated from chronically colonised cystic fibrosis patients receiving azole therapy - Corrected Proof

Adelina Amorim, Luísa Guedes-Vaz, Ricardo Araujo — 2010-02-08

Abstract: Exposure of Aspergillus fumigatus to stressful antifungal therapies may result in decreased susceptibility. The aim of the present work was to evaluate the susceptibility to azole and non-azole antifungals of 159 isolates of A. fumigatus collected from cystic fibrosis (CF) patients receiving azole antifungal therapy. The genetic diversity of the fungal isolates was assessed using microsatellite genotyping, and some strains were found in patient's sputum samples more than 4 years apart. No resistant isolates [minimal inhibitory concentration (MIC)/minimal effective concentration (MEC)≥4μg/mL] were identified to the antifungals amphotericin B, caspofungin, itraconazole and voriconazole. A single A. fumigatus isolate was identified outside of the epidemiological cut-off of 0.25μg/mL for posaconazole. Susceptibility of the recurrent isolates was in agreement with the susceptibility of the first isolate identified (100% essential agreement). Even after azole exposure, several recurrent A. fumigatus strains were detected in the subsequent sputum samples. Development of resistance in A. fumigatus to antifungals appears to be rare amongst CF patients. However, it remains crucial to evaluate the importance of antifungal agents for allergic fungal diseases.

High efficacy of clofazimine and its synergistic effect with amikacin against rapidly growing mycobacteria - Corrected Proof

Gwan-Han Shen, Bo-Da Wu, Shiau-Ting Hu, Chen-Fu Lin, Kun-Ming Wu, Jiann-Hwa Chen — 2010-02-08

Abstract: The aim of this study was to determine whether clofazimine, dapsone and cycloserine may be suitable antimicrobial agents for the treatment of infections due to rapidly growing mycobacteria (RGM). The antimicrobial activity of the three drugs against 117 Mycobacterium abscessus isolates, 48 Mycobacterium fortuitum isolates and 20 Mycobacterium chelonae isolates was evaluated based on their broth microdilution minimal inhibitory concentrations (MICs) against the isolates. Clofazimine was highly efficacious against these RGM. The vast majority of M. abscessus, M. fortuitum and M. chelonae isolates (99.1%, 91.7% and 100%, respectively) had clofazimine MICs of ≤1mg/L. MIC50 values (MIC for 50% of the organisms) of clofazimine against the isolates ranged from 0.25mg/L to 0.5mg/L and MIC90 values (MIC for 90% of the organisms) ranged from 0.5mg/L to 1.0mg/L. Cycloserine and dapsone had little or no activity against the isolates. The effects of combined application of clofazimine and amikacin on 40 M. abscessus isolates, 48 M. fortuitum isolates and 20 M. chelonae isolates were evaluated. Addition of 0.25× MIC of amikacin for the isolates to clofazimine reduced clofazimine MICs in all of the M. abscessus and M. chelonae isolates and in 48% of the M. fortuitum isolates tested. Clofazimine, either alone or combined with amikacin, may serve as a promising drug for the treatment of RGM infections.

Mechanisms of resistance to ciprofloxacin, ampicillin/sulbactam and imipenem in Acinetobacter baumannii clinical isolates in Taiwan - Corrected Proof

2010-02-08

Abstract: Nosocomial infections caused by multidrug-resistant (MDR) Acinetobacter baumannii have been increasing in recent years, posing a threat to public health worldwide. The susceptibility to eight antimicrobial agents of 35 clinical A. baumannii isolates from Taiwan was tested. Isolates were examined by polymerase chain reaction (PCR) and sequencing for β-lactamase genes and mutations in the gyrA and parC genes. Expression of AdeB, an efflux pump protein, was evaluated by real-time quantitative PCR. The level of adeB expression correlated with resistance to ciprofloxacin and ampicillin/sulbactam in A. baumannii isolates. Almost all isolates with full resistance to ciprofloxacin had both high adeB expression and point mutations in parC and gyrA, but 4 intermediate-resistant isolates had only high adeB expression without point mutations in gyrA or parC, in contrast to 18 susceptible isolates with low adeB expression and without mutations in gyrA or parC. Sixteen isolates (45.7%) carrying a type 1 integron were MDR as well as being more resistant to imipenem, amikacin, gentamicin, ceftazidime or cefepime than those without the integron. The class 1 integron in A. baumannii carried different resistance gene cassettes, including 5′CS-blaIMP-1–aadA4–3′CS, 5′CS–aacA4–aadA1–3′CS and 5′CS–aacC1–aadA1–3′CS. In conclusion, expression of the adeB gene was associated with resistance to ciprofloxacin and ampicillin/sulbactam in A. baumannii. Multiple mutations in gyrA and parC also played a role in ciprofloxacin resistance. The major metallo-β-lactamase contributing to imipenem resistance in A. baumannii in Taiwan was blaIMP-1, which was carried by the class 1 integron. The class 1 integron was associated with the MDR phenotype in A. baumannii.

Carriage of genes for various extended-spectrum β-lactamases: a novel resistance strategy of Klebsiella pneumoniae in Poland - Corrected Proof

2010-02-08

Abstract: Among 110 randomly sampled strains from a collection of 247 extended-spectrum β-lactamase (ESBL)-producing clinical isolates of Klebsiella pneumoniae collected from hospitalised children in three paediatric hospitals in Poland, 64 strains (58.2%) with multiple ESBLs were found, including five non-clonal strains (4.5%) harbouring bla genes for ESBLs of three families (CTX-M, SHV and TEM). This is the first report of the emergence of triple ESBL-producing K. pneumoniae in Poland. In addition, K. pneumoniae strains harbouring bla genes for TEM-130 and TEM-132 ESBLs were detected in Poland for the first time. Epidemiological analysis of the multiple ESBL-producing K. pneumoniae isolates by pulsed-field gel electrophoresis (PFGE) revealed a relatively high genetic diversity between isolates producing the same combination of enzymes. Clonally related strains were uncommon.

Activity of tigecycline against meticillin-resistant Staphylococcus aureus (MRSA) from respiratory tract sources - Corrected Proof

Stephen P. Hawser — 2010-02-08

Meticillin-resistant Staphylococcus aureus (MRSA) is a recognised causative agent of community-acquired pneumonia (CAP) whose incidence and resistance to antibiotics has been increasing recently . Tigecycline is approved in the USA for treatment of MRSA in complicated intra-abdominal and complicated skin and skin-structure infections and was recently approved for the treatment of CAP in 2008, although the latter indication does not include MRSA . The Tigecycline Evaluation Surveillance Trial (T.E.S.T.) monitors the global in vitro activity of tigecycline compared with several other agents. This study summarises the in vitro activity of tigecycline and appropriate comparators against MRSA from community-associated (CA) and hospital-associated (HA) respiratory tract infections (RTIs).

Differentiation of viral and bacterial pneumonia in influenza - Corrected Proof

Michael Eisenhut — 2010-02-08

In a recent Editorial , which commented on an article highlighting the predominant role of bacterial pneumonia as a cause of death in pandemic influenza, it was suggested to use C-reactive protein (CRP) to differentiate between viral and bacterial pneumonia. It was pointed out that the decision to commence antibacterial agents will have to be made based on clinical judgement in most cases.

Efficacy of voriconazole in a murine model of invasive paecilomycosis - Corrected Proof

M. Mar Rodríguez, F. Javier Pastor, Carolina Serena, Josep Guarro — 2010-02-03

Abstract: We studied the efficacy of voriconazole (VRC) and amphotericin B (AMB) in an immunosuppressed murine model of disseminated infection by two strains of Paecilomyces lilacinus. Mice were treated with VRC 60mg/kg/day orally or AMB 3mg/kg/day intraperitoneally, beginning 1 day after infection and continuing for 9 days. To avoid rapid clearance of VRC, animals receiving VRC and the control group were given grapefruit juice instead of water. VRC significantly prolonged survival with respect to the group treated with AMB and the control group for both strains (P=0.005 and P<0.0001, respectively, for strain FMR 5522; and P=0.0002 and P<0.0001, respectively, for strain FMR 8252). VRC reduced the fungal load in the spleen, kidneys and liver of infected mice for both strains tested. Survival of mice challenged with strain FMR 8252 treated with AMB did not differ from that of the control group (P=0.223), being worse than that of the mice treated with VRC (P=0.0002). AMB was not able to reduce the tissue burden in any organ with respect to the control group for both strains studied.

Synthetic antimicrobial peptide L8 (MHLHKTSRVTLYLL) has membrane permeabilisation and bacterial aggregation activity - Corrected Proof

Evelin Loit, Maxwell T. Hincke, Illimar Altosaar — 2010-02-03

Antimicrobial peptides (AMPs) have evolved for defence against invading microorganisms. AMPs contribute to host protection primarily by permeabilisation and depolarisation of bacterial plasma membranes, followed by cell lysis and death. Other mechanisms include opsonisation and agglutination of target bacteria .

Patterns of antimicrobial therapy in severe nosocomial infections: empiric choices, proportion of appropriate therapy, and adaptation rates—a multicentre, observational survey in critically ill patients - Corrected Proof

2010-02-01

Abstract: This prospective, observational multicentre (n=24) study investigated relationships between antimicrobial choices and rates of empiric appropriate or adequate therapy, and subsequent adaptation of therapy in 171 ICU patients with severe nosocomial infections. Appropriate antibiotic therapy was defined as in vitro susceptibility of the causative pathogen and clinical response to the agent administered. In non-microbiologically documented infections, therapy was considered adequate in the case of favourable clinical response <5 days. Patients had pneumonia (n=127; 66 ventilator-associated), intra-abdominal infection (n=23), and bloodstream infection (n=21). Predominant pathogens were Pseudomonas aeruginosa (n=29) Escherichia coli (n=26), Staphylococcus aureus (n=22), and Enterobacter aerogenes (n=21). In 49.6% of infections multidrug-resistant (MDR) bacteria were involved, mostly extended-spectrum β-lactamase (EBSL)-producing Enterobacteriaceae and MDR non-fermenting Gram-negative bacteria. Prior antibiotic exposure and hospitalisation in a general ward prior to ICU admission were risk factors for MDR. Empiric therapy was appropriate/adequate in 63.7% of cases. Empiric schemes were classified according to coverage of (i) ESBL-producing Enterobacteriaceae and non-fermenting Gram-negative bacteria (“meropenem-based”), (ii) non-fermenting Gram-negative bacteria (schemes with an antipseudomonal agent), and (iii) first-line agents not covering ESBL-Enterobacteriaceae nor non-fermenting Gram-negative bacteria. Meropenem-based schemes allowed for significantly higher rates of appropriate/adequate therapy (p<0.001). This benefit remained when only patients without risk factors for MDR were considered (p=0.021). In 106 patients (61%) empiric therapy was modified: in 60 cases following initial inappropriate/inadequate therapy, in 46 patients in order to refine empiric therapy. In this study reflecting real-life practice, first-line use of meropenem provided significantly higher rates of the appropriate/adequate therapy, irrespective of presence of risk factors for MDR.

Corrigendum to “Cytotoxic effect of amide derivatives of trifluoromethionine against the enteric protozoan parasite Entamoeba histolytica” [Int. J. Antimicrob. Agents 31 (2010) 56–61] - Corrected Proof

2010-01-29

The authors regret that critical mistakes were published in of the above mentioned manuscript. The correct is reproduced below. The authors would like to apologise for any inconvenience this may have caused to the readers of the journal.

Differences in carbapenem resistance genes among Acinetobacterbaumannii, Acinetobacter genospecies 3 and Acinetobacter genospecies 13TU in Taiwan - Corrected Proof

2010-01-27

Abstract: A total of 81 clinical isolates of the three clinically important Acinetobacter spp., namely Acinetobacter baumannii, Acinetobacter genospecies 3 and Acinetobacter genospecies 13TU, were analysed for differences in carbapenem resistance genes. Of the 81 isolates, 40 (49%) were resistant to carbapenems. Most A. baumannii isolates (47/53, 88.7%) contained the ISAba1–blaOXA-51-like gene and exhibited a higher minimum inhibitory concentration to imipenem than A. baumannii without the ISAba1 element. All four carbapenem-resistant A. genospecies 3 isolates contained blaIMP-1 and an ISAba3–blaOXA-58-like gene. Three A. genospecies 13TU isolates contained an ISAba3–blaOXA-58-like and either a blaIMP-1 or a blaVIM-11 gene. The five blaIMP-1-containing strains were resistant to imipenem and were positive for metallo-β-lactamase (MBL) activity by the Etest, and the two blaVIM-11-containing strains were susceptible to imipenem and were MBL-negative by Etest. Imipenem hydrolysis tests showed that the blaIMP-1-containing strains exhibited much higher imipenem-hydrolysing activity than the two blaVIM-11-containing strains. No transcripts of blaVIM-11 or blaOXA-58-like genes were detected. Analysis of outer membrane proteins showed that OprD was absent in the only blaIMP-1-containing A. genospecies 13TU strain owing to the presence of a premature stop codon in the oprD gene. In summary, several differences were detected between the carbapenem resistance genes of clinical Acinetobacter spp. in Taiwan, and loss of OprD may be associated with imipenem resistance in A. genospecies 13TU.

Combination of caspofungin or anidulafungin with antimicrobial peptides results in potent synergistic killing of Candida albicans and Candida glabrata in vitro - Corrected Proof

Mark R. Harris, Peter J. Coote — 2010-01-27

Abstract: Administering synergistic combinations of antifungals could be a route to overcome problems with toxicity and the development of resistance. Combination of the echinocandins caspofungin or anidulafungin with a range of structurally diverse antimicrobial peptides resulted in potent synergistic killing of Candida spp. in vitro. Fungicidal synergy was measured by calculating fractional inhibitory concentration indices from checkerboard assays as well as loss of viability. Inhibitory combinations of the antifungals did not induce cytotoxicity in vitro. However, in a murine model of systemic candidiasis, co-administration of caspofungin with one example of the cationic peptides tested, ranalexin, did not show enhanced efficacy compared with the single treatments alone. Further study using alternative peptides will identify whether this combination approach could represent a novel treatment for fungal pathogens.

Predictors of acute kidney injury associated with intravenous colistin treatment - Corrected Proof

2010-01-20

Abstract: Colistimethate sodium (CMS) was recently re-introduced into clinical practice as a last resort for the treatment of nosocomial infections caused by multiresistant bacteria. This retrospective cohort study was designed to identify predictors of acute kidney injury (AKI) associated with intravenous (i.v.) CMS treatment. From March 2007 to July 2008, 71 adult patients receiving CMS for ≥72h were enrolled. AKI was defined using Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) criteria according to serum creatinine. The median total dose of CMS was 54.3mg/kg (range 27.5–94.5mg/kg). AKI developed in 38 patients (53.5%). Cox regression analysis based of cumulative CMS dose (mg/kg) identified four independent predictors of AKI: male sex [hazard ratio (HR)=3.55, 95% confidence interval (CI), 1.47–8.55]; concomitant use of a calcineurin inhibitor (HR=6.74, 95% CI 2.49–18.24); hypoalbuminaemia (serum albumin level <2.0g/dL) (HR=6.29, 95% CI 2.04–19.39); and hyperbilirubinaemia (total bilirubin level >5mg/dL) (HR=3.53, 95% CI 1.17–10.71). In conclusion, AKI was a common complication of i.v. CMS treatment. Male sex, concomitant use of calcineurin inhibitors, hypoalbuminaemia and hyperbilirubinaemia were independent predictors of AKI. The effect of AKI on patient outcomes was not determined.

Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli - Corrected Proof

2010-01-13

Abstract: To clarify the molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli, the murA, glpT, uhpT, uhpA, ptsI and cyaA genes were sequenced from six fosfomycin-resistant isolates. Two strains were found to harbour a mutation in the murA gene that leads to an amino acid substitution (Asp369Asn or Leu370Ile) in the target protein. The remaining four strains carried specific mutations in the glpT gene; one strain possessed a mutation and the other three strains possessed truncated versions of the GlpT transporter owing either to the presence of insertion sequences or a deletion in the coding region of the gene. Two of the strains with truncated GlpT had also lost the entire uhpT gene, which encodes another fosfomycin transporter. Uptake of specific substrates for the transporters was either totally blocked or reduced in strains possessing truncated forms of GlpT or those lacking the uhpT gene. Escherichia coli strains expressing an amino-acid-substituted MurA were at least eight-fold more resistant to fosfomycin than the strain overproducing wild-type MurA. In conclusion, novel amino acid substitutions in MurA or the loss of function of transporters were identified as mechanisms of fosfomycin resistance in clinical isolates of E. coli.

Phenothiazinium–fluoroquinolone drug conjugates - Corrected Proof

2010-01-11

Abstract: Synthesis and antibacterial screening of a homologous series of 3-dialkylaminophenothiazinium-7-norfloxacin conjugates was carried out alongside a corresponding series of symmetrical methylene blue derivatives. The norfloxacin conjugates maintained typical methylene blue derivative photoproperties, such as long wavelength absorption, but produced no measurable singlet oxygen in the standard assay and provided no significant increase in the magnitude of photoantibacterial action, this being similar to the methylene blue homologues, although both the conjugates and homologues were considerably more active than methylene blue itself both against Staphylococcus aureus and Escherichia coli. DNA binding via intercalation was considerably greater for the series of norfloxacin conjugates than for the methylene blue homologues.

Molecular epidemiology of Escherichia coli producing CTX-M β-lactamases: the worldwide emergence of clone ST131 O25:H4 - Corrected Proof

Gisele Peirano, Johann D.D. Pitout — 2010-01-08

Abstract: Since 2000, Escherichia coli producing CTX-M enzymes have emerged worldwide as important causes of community-onset urinary tract and bloodstream infections owing to extended-spectrum β-lactamase (ESBL)-producing bacteria. Molecular epidemiological studies suggested that the sudden worldwide increase of CTX-M-15-producing E. coli was mainly due to a single clone (ST131) and that foreign travel to high-risk areas, such as the Indian subcontinent, might in part play a role in the spread of this clone across different continents. Empirical antibiotic coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract, especially if the patient recently travelled to a high-risk area. If this emerging public health threat is ignored, it is possible that the medical community may be forced, in the near future, to use carbapenems as the first choice for the empirical treatment of serious infections associated with urinary tract infections originating from the community.

Synergistic effects of dexamethasone and quinolones on human-derived tendon cells - Corrected Proof

2009-12-25

Abstract: Quinolones and glucocorticoids are frequently used drugs that may cause tendinopathy as a rare adverse effect. We exposed human tenocyte cultures to the steroid dexamethasone alone or in combination with either ciprofloxacin or levofloxacin at concentrations of 3mg/L and 10mg/L. At concentrations corresponding to peak levels in plasma and tissues during therapy (ca. 3–10mg/L), ciprofloxacin caused a significant decrease in collagen type I and the β1-integrin receptor. In contrast, no corresponding effect was induced by 3mg/L levofloxacin. With both quinolones at 3mg/L and 10mg/L, the amount of matrix metalloproteinase-1 (MMP-1) and MMP-13 was increased. In addition, 3mg/L ciprofloxacin and 10mg/L levofloxacin activated caspase-3. Apoptotic changes were confirmed by electron microscopy. Incubation of human tenocytes with dexamethasone decreased the main matrix protein collagen type I, the transmembrane β1-integrin receptor and the cytoskeleton protein vinculin, but only at the high concentrations tested (0.1μM or 10μM). Concentrations of 0.1μM and 10μM dexamethasone increased the amount of MMPs and activated caspase-3 as an indicator of apoptosis. Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints. The clinical observations of an increased risk of quinolone-induced tendinopathy by glucocorticoids are supported by these in vitro data.

The designer proline-rich antibacterial peptide A3-APO is effective against systemic Escherichia coli infections in different mouse models - Corrected Proof

2009-12-23

Abstract: Antimicrobial peptides are considered to be viable alternatives to conventional antibiotics. However, they rarely show systemic efficacy in animal models when added at non-toxic doses. The dimer A3-APO was designed to attack both the bacterial membrane and the Enterobacteriaceae-specific domain of the heat shock protein DnaK in order to reduce toxicity whilst maintaining activity. The peptide exhibited a minimal inhibitory concentration (MIC) range of 2–128mg/L against 28 clinical Escherichia coli, Klebsiella pneumoniae and Salmonella enterica serovar Typhimurium strains, with a median MIC of 30mg/L. At this concentration, A3-APO was bactericidal to E. coli 5770, a fluoroquinolone-resistant extended-spectrum β-lactamase-producing strain. The No Observed Adverse Effect Limit (NOAEL) at repeated intraperitoneal peptide administration was 20mg/kg. When administered at this dose three times starting immediately after E. coli Neumann infection, A3-APO cured 100% of mice in a standard bacteraemia model used by the pharmaceutical industry. In a more stringent assay, when treatment started after E. coli 5770 bacteraemia had already been established, three doses of 10mg/kg A3-APO prolonged early survival at a rate similar to that of imipenem and reduced the bacterial counts to base level. When the second assay was repeated in kidney clearance conditions resembling those in humans, 10mg/kg A3-APO was as efficacious as imipenem in the long-term. The increased in vivo efficacy compared with the in vitro bactericidal figures can potentially be explained by the generally observable immunostimulatory properties of antimicrobial peptides. Peptide A3-APO shows promising features as a member in our antibiotic arsenal against multidrug-resistant bacterial pathogens.

Evaluation of azithromycin, trovafloxacin and grepafloxacin as prophylaxis against experimental murine Brucella melitensis infection - Corrected Proof

2009-12-21

Abstract: The prophylactic potential of the azalide azithromycin as well as the fluoroquinolones trovafloxacin and grepafloxacin was assessed for the control of infection with Brucella melitensis in an experimental mouse model, determined by reduction in splenic bacterial burden. Trovafloxacin showed limited protective efficacy when administered 2h following a low-dose B. melitensis challenge, whereas grepafloxacin was ineffective. In comparison, azithromycin provided significant control of infection both following low- and high-dose challenges. Overall, the data confirm the potential utility of azithromycin in the prophylaxis of brucellosis and suggest that neither trovafloxacin nor grepafloxacin would likely be valuable for post-exposure prophylaxis of Brucella infection.

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.