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Showing papers in "Journal of Antimicrobial Chemotherapy in 2007"


Journal ArticleDOI
TL;DR: A broadly disseminated, CTX-M-15-positive and virulent E. coli clonal group with highly homogeneous virulence genotypes and subgroups exhibiting highly similar PFGE profiles is described, suggesting recent emergence.
Abstract: BACKGROUND: Concomitant with the recent emergence of CTX-M-type extended-spectrum beta-lactamases (ESBLs), Escherichia coli has become the enterobacterial species most affected by ESBLs. Multiple locales are encountering CTX-M-positive E. coli, including specifically CTX-M-15. To gain insights into the mechanism underlying this phenomenon, we assessed clonality and diversity of virulence profiles within an international collection of CTX-M-15-positive E. coli. METHODS: Forty-one ESBL-positive E. coli isolates from eight countries and three continents (Europe, Asia and North America) were selected for study based on suspected clonality. Phylogenetic group, ERIC2 PCR profile, O H serotype, AmpC variant and antibiotic susceptibility were determined. Multilocus sequence typing (MLST) and PFGE provided additional discrimination. Virulence potential was inferred by detection of 46 virulence factor (VF) genes. RESULTS: Thirty-six (88%) of the 41 E. coli isolates exhibited the same set of core characteristics: phylogenetic group B2, ERIC2 PCR profile 1, serotype O25:H4, AmpC EC6, ciprofloxacin resistance and MLST profile ST131. By PFGE, the 36 isolates constituted one large cluster at the 68% similarity level; this comprised 17 PFGE groups (defined at 85% similarity), some of which included strains from different countries. The 36 isolates exhibited highly (91% to 100%) similar VF profiles. CONCLUSIONS: We describe a broadly disseminated, CTX-M-15-positive and virulent E. coli clonal group with highly homogeneous virulence genotypes and subgroups exhibiting highly similar PFGE profiles, suggesting recent emergence. Understanding how this clone has emerged and successfully disseminated within the hospital and community, including across national boundaries, should be a public health priority.

800 citations


Journal ArticleDOI
TL;DR: Since polymyxins will be increasingly used for the treatment of infections caused by MDR bacteria, clinical pharmacokinetic, pharmacodynamic and toxicodynamic studies underpinning the optimal use of these drugs are urgently required.
Abstract: Polymyxins have re-emerged in clinical practice owing to the dry antibiotic development pipeline and worldwide increasing prevalence of nosocomial infections caused by multidrug-resistant (MDR) Gramnegative bacteria. Polymyxin B and colistin (polymyxin E) have been ultimately considered as the lastresort treatment of such infections. Microbiological, pharmacokinetic, pharmacodynamic and clinical data available for polymyxin B are reviewed in this paper. Polymyxin B has rapid in vitro bactericidal activity against major MDR Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Acquired resistance to this agent is still rare among these pathogens. However, optimized dosage regimens are not known yet. Good clinical outcomes have been observed in the majority of the patients treated with intravenous polymyxin B in recent studies. However, these studies failed to provide definitive conclusions due to limitations of study design and additional clinical trials are required. Although combination therapy may be an attractive option based on some currently available in vitro data, clinical data supporting such recommendations are lacking. Since polymyxins will be increasingly used for the treatment of infections caused by MDR bacteria, clinical pharmacokinetic, pharmacodynamic and toxicodynamic studies underpinning the optimal use of these drugs are urgently required.

718 citations


Journal ArticleDOI
Ian Chopra1
TL;DR: The clinical incidence of silver resistance remains low, and emergence of resistance can be minimized if the level of silver ions released from products is high and the bactericidal activity rapid.
Abstract: Silver first gained regulatory approval for use as an antimicrobial agent in the early 20th century, but its usage diminished with the introduction of antibiotics in the 1940s. Recently, however, topical silver has gained popularity once again, principally in the management of open wounds. This has been largely due to the spread of methicillin-resistant Staphylococcus aureus and the resultant reduction in first-line antibiotic prescribing. The increase in the use of topical silver has raised issues concerning silver resistance, together with questions about the standardization of antimicrobial testing methods for silver. Issues related to silver product testing include a failure to establish standard procedures for determining MIC values, an absence of recognized breakpoints, a lack of conformity in the way different products release silver and variations in the effects of microbiological media on silver release and the measurement of inhibitory activity. The clinical incidence of silver resistance remains low, and emergence of resistance can be minimized if the level of silver ions released from products is high and the bactericidal activity rapid.

690 citations


Journal ArticleDOI
TL;DR: In Enterobacteriaceae bacteraemia, ESBL production is associated with increased mortality and delay in effective therapy, however, lack of controlled studies limits interpretation regarding causality, and further controlled studies are required.
Abstract: Objectives: We performed a systematic review and meta-analysis to examine the impact of extended-spectrum b-lactamase (ESBL) production on mortality and delay in effective therapy in Enterobacteriaceae bacteraemia. Methods: We searched the PubMed database using the terms ‘bacteremia or bloodstream’ and ‘ESBL or extended-spectrum beta-lactamase’. Included studies contained numbers of and mortality figures for patients with bacteraemia caused by ESBL producers and non-producers. Data extracted included crude relative risk (RR), adjusted odds ratio and 95% confidence intervals (CIs) for mortality and delayed effective therapy. Results were pooled using a random effects model. Results: Sixteen studies met inclusion criteria. Meta-analysis of crude RRs demonstrated significantly increased mortality in ESBL-associated bacteraemia (pooled RR 1.85, 95% CI 1.39–2.47, P < 0.001). However, only one study reported RR controlled for confounding. Ten studies reported comparative data on delay in effective therapy. Meta-analysis of crude RRs demonstrated significantly increased incidence of delay in effective therapy in ESBL-associated bacteraemia (pooled RR 5.56, 95% CI 2.94– 10.51, P < 0.001). Conclusions: In Enterobacteriaceae bacteraemia, ESBL production is associated with increased mortality and delay in effective therapy. However, lack of controlled studies limits interpretation regarding causality, and further controlled studies are required.

586 citations


Journal ArticleDOI
TL;DR: A fast and reliable technique for rapid screening of qnr-positive strains to be used for epidemiological surveys is reported, with a low prevalence of Qnr determinants among ESBL-producing Enterobacteriaceae was identified in the study with Kuwaiti isolates.
Abstract: Results: In optimized conditions, all positive controls (used separately or mixed) confirmed the specificity of the PCR primers. Out of 64 isolates, only 3 isolates were positive for a qnrB-like gene (4.7%), whereas no qnrA-like and qnrS-like gene was detected. A qnrB2 gene was detected in an Enterobacter cloacae K34 (SHV-121) isolate, whereas qnrB1-like (termed qnrB7) and qnrB6-like (termed qnrB8) genes were identified from E. cloacae K37 (SHV-121) and Citrobacter freundii K70 (VEB-1b1) isolates, respectively. Conclusions: We report here a fast and reliable technique for rapid screening of qnr-positive strains to be used for epidemiological surveys. A low prevalence of Qnr determinants among ESBL-producing Enterobacteriaceae was identified in the study with Kuwaiti isolates.

566 citations


Journal ArticleDOI
TL;DR: The use of bacterial resistance modifiers such as EPIs could facilitate the re-introduction of therapeutically ineffective antibiotics back into clinical use such as ciprofloxacin and might even suppress the emergence of MDR strains.
Abstract: The rapid spread of bacteria expressing multidrug resistance (MDR) has necessitated the discovery of new antibacterials and resistance-modifying agents. Since the initial discovery of bacterial efflux pumps in the 1980s, many have been characterized in community- and hospital-acquired Gram-positive and Gram-negative pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and, more recently, in mycobacteria. Efflux pumps are able to extrude structurally diverse compounds, including antibiotics used in a clinical setting; the latter are rendered therapeutically ineffective. Antibiotic resistance can develop rapidly through changes in the expression of efflux pumps, including changes to some antibiotics considered to be drugs of last resort. It is therefore imperative that new antibiotics, resistance-modifying agents and, more specifically, efflux pump inhibitors (EPIs) are characterized. The use of bacterial resistance modifiers such as EPIs could facilitate the re-introduction of therapeutically ineffective antibiotics back into clinical use such as ciprofloxacin and might even suppress the emergence of MDR strains. Here we review the literature on bacterial EPIs derived from natural sources, primarily those from plants. The resistance-modifying activities of many new chemical classes of EPIs warrant further studies to assess their potential as leads for clinical development.

486 citations


Journal ArticleDOI
TL;DR: This meta-analysis shows a clear association between exposure to antibiotics and MRSA isolation, and may be useful for researchers in designing future studies and for policy decision-making on the appropriate management of antibiotic therapies.
Abstract: Background: Current evidence does not provide a clear definition of the association between methicillinresistant Staphylococcus aureus (MRSA) isolation and previous antibiotic use. A systematic review was performed to determine whether antibiotic exposure is a risk factor for the isolation of MRSA. Methods: MEDLINE and EMBASE databases were searched to identify studies published between 1976 and 2007 on the role of antibiotics as a risk factor for MRSA isolation in adult patients. The outcome of interest was MRSA isolation. Summary statistics were risk ratios (RR) comparing MRSA-positive patients to those without S. aureus isolation or with methicillin-susceptible S. aureus isolation. Results: Seventy-six studies, including a total of 24 230 patients, met the inclusion criteria. Antibiotic exposure was determined in the 126 + + 184 (mean + SD) days preceding MRSA isolation. The risk of acquiring MRSA was increased by 1.8-fold [95% confidence interval (CI), 1.7‐1.9; P < 0.001] in patients who had taken antibiotics. The RR for single classes of antibiotics was 3 (95% CI, 2.5‐3.5) for quinolones, 2.9 (95% CI, 2.4‐3.5) for glycopeptides, 2.2 (95% CI, 1.7‐2.9) for cephalosporins and 1.9 (95% CI, 1.7‐2.2) for other b-lactams. Significant heterogeneity was detected among studies. A regression analysis revealed that the heterogeneity was linked to the length of time in which antibiotic exposure was detected before MRSA isolation (more or less than 180 days).

424 citations


Journal ArticleDOI
TL;DR: Although the MICs of all agents appeared to be associated with increasing oxacillin MICs, the strongest associations were noted for vancomycin and linezolid.
Abstract: lin. MICs increased for vancomycin, linezolid and oxacillin (P < 0.0001); however, daptomycin MICs decreased slightly (P 5 0.0386). For vancomycin, linezolid and oxacillin, there were significant increases (P < 0.0001) in the percentage of isolates with MICs that were higher than the respective 2001 median MIC, but not for daptomycin (P 5 0.1361). Oxacillin MICs were associated with MICs of linezolid (r 5 0.364, P < 0.0001), vancomycin (r 5 0.353, P < 0.0001) and daptomycin (r 5 0.106, P 5 0.0063). Conclusions: Oxacillin, vancomycin and linezolid MICs increased over time. For vancomycin and linezolid, these MIC increases were not reliably detected by percentage susceptibility as they occurred below the susceptibility breakpoint. Although the MICs of all agents appeared to be associated with increasing oxacillin MICs, the strongest associations were noted for vancomycin and linezolid.

407 citations


Journal ArticleDOI
TL;DR: This review is focused on the current knowledge of porins and efflux pump(s) in this microorganism and the ability to acquire multidrug resistance.
Abstract: Acinetobacter baumannii is an opportunistic pathogen, causing infections mainly in patients in intensive care units where the extensive use of antimicrobial agents can select for the emergence of multiresistant strains. In fact, since strains resistant to all antimicrobial agents have been reported, A. baumannii is considered the paradigm of multiresistant bacteria. Both acquired and intrinsic resistance can contribute to multiresistance. The ability to acquire multidrug resistance can be due to either the acquisition of genetic elements carrying multiple resistant determinants or mutations affecting the expression of porins and/or efflux pump(s), which can affect unrelated antimicrobial agents. Meanwhile, intrinsic resistance can be generated by the interplay of decreased permeability and constitutive expression of active efflux systems and it too can affect unrelated antimicrobial agents. This review is focused on the current knowledge of porins and efflux pump(s) in this microorganism.

384 citations


Journal ArticleDOI
TL;DR: This new strategy, based on a single multiplex PCR reaction, is adequate for the rapid assignment of all major subtypes of SCCmec type IV described so far and also the new subtype IVh characteristic of EMRSA-15.
Abstract: Methods: Seven primer pairs were designed to detect the ccrB allotype 2 (internal positive control), the five polymorphic J1 regions described so far for SCCmec type IV and the new J1 region specific for EMRSA-15. Primer sets were tested for specificity and robustness with prototype strains for each subtype of SCCmec type IV. The multiplex PCR conditions were optimized in a trial–error approach. Results: The seven prototype strains for the earlier described subtypes of SCCmec type IV and the EMRSA-15 prototype strain were correctly characterized by our strategy. Moreover, 13 diverse SCCmec type IV strains could be assigned to a subtype of SCCmec type IV and 5 EMRSA-15 strains were assigned to the new subtype IVh. One strain could not be assigned to an SCCmec type IV subtype because of the absence of amplification of the specific J1 region. Conclusions: This new strategy, based on a single multiplex PCR reaction, is adequate for the rapid assignment of all major subtypes of SCCmec type IV described so far and also the new subtype IVh characteristic of EMRSA-15. This strategy complements well the previously described multiplex PCR assay for the rapid assignment of SCCmec types.

341 citations


Journal ArticleDOI
TL;DR: Finding of acquired resistance genes in isolates intended for probiotic or nutritional use highlights the importance of antimicrobial susceptibility testing in documenting the safety of commercial LAB.
Abstract: Results: Tentative ECOFF values of 13 antibiotics were determined for up to 12 LAB species. Generally, LAB were susceptible to penicillin, ampicillin, ampicillin/sulbactam, quinupristin/dalfopristin, chloramphenicol and linezolid. LAB exhibited broad or partly species-dependent MIC profiles of trimethoprim, trimethoprim/sulfamethoxazole, vancomycin, teicoplanin and fusidic acid. Three probiotic Lactobacillus strains were highly resistant to streptomycin. Although erythromycin, clindamycin and oxytetracycline possessed high antimicrobial activities, 17 Lactobacillus isolates were resistant to one or more of these antibiotics. Eight of them, including six probiotic and nutritional cultures, possessed erm(B) and/or tet(W), tet(M) or unidentified members of the tet(M) group. In vitro intra- and interspecies filter-mating experiments failed to show transfer of resistance determinants.

Journal ArticleDOI
TL;DR: Over the last decades, numerous papers have appeared--and still are appearing--that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms.
Abstract: Over the last decades, numerous papers have appeared-and still are appearing-that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.

Journal ArticleDOI
TL;DR: Inhibition of bacterial efflux mechanisms appears to be a promising target in order to increase the intracellular concentration of antibiotics that are expelled by efflux pumps, restore the drug susceptibility of resistant clinical strains, and reduce the capability for acquired additional resistance.
Abstract: After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance. Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure-activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial efflux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition. Recent studies of pump-substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the efflux mechanisms and, finally, may result in a clinically useful molecule.

Journal ArticleDOI
TL;DR: The authors' data indicate that subgroup identification of A. baumannii may aid selection of appropriate antimicrobial agents for the treatment of Acinetobacter infections, and indicates that antimicrobial resistance rates varied markedly between subgroups.
Abstract: Objectives: To investigate antimicrobial resistance in clinical isolates of Acinetobacter spp. from two Korean hospitals. Methods: Two hundred and sixty-five isolates of Acinetobacter spp. from two Korean hospitals were collected and were identified to species level using partial rpoB gene sequences. Antimicrobial susceptibility testing was performed using a broth microdilution method. Results: rpoB gene sequences indicated that 214 isolates (80.8%) were Acinetobacter baumannii, and allowed these to be classified into three subgroups (I, II and III); 142 isolates (53.6%) belonged to subgroup I, 54 (20.4%) to subgroup II and 18 (6.8%) to subgroup III. Forty-eight isolates (18.1%) and 74 isolates (27.9%) were resistant to polymyxin B and colistin, respectively. However, antimicrobial resistance rates varied markedly between subgroups. While A. baumannii subgroup I showed low resistance rates to polymyxin B and colistin (2.1% and 7.0%, respectively), subgroups II and III showed high resistance rates to these antibiotics (38.9% and 64.8% in subgroup II and 72.2% and 88.9%, in subgroup III, respectively). Multidrug resistance was also significantly more frequent in subgroup I (45.1%) than in subgroups II and III (13.0% and 16.7%, respectively). Conclusions: Our data indicate that subgroup identification of A. baumannii may aid selection of appropriate antimicrobial agents for the treatment of Acinetobacter infections.

Journal ArticleDOI
TL;DR: High resistance rates to tigecycline, and higher than previously described MICs, in multiple clones of MDR A. baumannii are reported, and these findings are worrisome.
Abstract: Objectives Multidrug-resistant (MDR) Acinetobacter baumannii is increasing in our hospital and worldwide, raising the necessity of finding effective therapies. We aimed to evaluate the in vitro activity of tigecycline against MDR A. baumannii clones isolated before tigecycline was used in our institution. Methods Eighty-two unique patient clinical isolates of multidrug-resistant A. baumannii collected in 2003 were studied. Species identification and antibiotic susceptibilities were determined by Vitek-2. Tigecycline MIC was determined by Etest. Clonal relatedness was determined by PFGE. Results MDR A. baumannii possessed 19 different pulsotypes. Sixty-six percent of the isolates were resistant to tigecycline, 12% were intermediate and 22% were susceptible. The MIC(50) and MIC(90) of tigecycline were 16 and 32 mg/L, respectively, with a wide MIC range of 1-128 mg/L. Variability in MIC of tigecycline was evident between and within the same pulsotype. Conclusions We report here high resistance rates to tigecycline, and higher than previously described MICs, in multiple clones of MDR A. baumannii. As tigecycline represents a new treatment choice for infections caused by A. baumannii, these findings are worrisome.

Journal ArticleDOI
TL;DR: Class A carbapenemases hydrolyse penicillins, classical cephalosporins, monobactam, and imipenem and meropenem, and the enzymes are divided into four phenotypically different groups, namely group 2br, 2be, 2e and 2f, according to the Bush-Jacoby-Medeiros classification system.
Abstract: Carbapenems, such as imipenem and meropenem, are most often used to treat infections caused by enterobacteria that produce extended-spectrum beta-lactamases, and the emergence of enzymes capable of inactivating carbapenems would therefore limit the options for treatment. Carbapenem resistance in Enterobacteriaceae is rare, but class A beta-lactamases with activity against the carbapenems are becoming more prevalent within this bacterial family. The class A carbapenemases can phylogenetically be segregated into six different groups of which four groups are formed by members of the GES, KPC, SME, IMI/NMC-A enzymes, while SHV-38 and SFC-1 each separately constitute a group. The genes encoding the class A carbapenemases are either plasmid-borne or located on the chromosome of the host. The bla(GES) genes reside as gene cassettes on mainly class I integrons, whereas the bla(KPC) genes and a single bla(IMI-2) gene are flanked by transposable elements on plasmids. Class A carbapenemases hydrolyse penicillins, classical cephalosporins, monobactam, and imipenem and meropenem, and the enzymes are divided into four phenotypically different groups, namely group 2br, 2be, 2e and 2f, according to the Bush-Jacoby-Medeiros classification system. Class A carbapenemases are inhibited by clavulanate and tazobactam like other class A beta-lactamases.

Journal ArticleDOI
TL;DR: Selective pressure due to extensive or inadequate colistin use may lead to the emergence ofcolistin resistance among K. pneumoniae isolates, jeopardizing treatment options in the ICU, potentially increasing morbidity and mortality of critically ill patients and necessitating prudent use of colistIn.
Abstract: Objectives: Infections due to multidrug-resistant (MDR) Gram-negative pathogens in the ICU have prompted the use of colistin, an antibiotic forgotten for decades. The aim of this retrospective observational study was to record and present the emergence of colistin-resistant Klebsiella pneumoniae (CRKB) in a Greek ICU. Methods: In a new university tertiary hospital, the first patients admitted in the ICU were already colonized or infected with MDR pathogens, and this led to frequent colistin use as part of empirical or microbiologically documented therapy. Colistin resistance was defined as MIC >4 mg/L by the Etest method. All CRKB isolated in surveillance cultures or clinical specimens in the ICU during the period 2004-5 were recorded along with patients' characteristics. Results: Eighteen CRKB were isolated from 13 patients over a 16 month period, representing either colonizing or infective isolates. Patients' mean age was 70 years, with a mean APACHE II score at admission of 22. They all had a long hospitalization (median 69 days) and a long administration of colistin (median 27 days). Colistin-resistant isolates were implicated as pathogens in two bacteraemias, a ventilator-associated pneumonia and two soft tissue infections. Repetitive extragenic palindromic PCR identified six distinct clones, and horizontal transmission was also documented. Conclusions: Selective pressure due to extensive or inadequate colistin use may lead to the emergence of colistin resistance among K. pneumoniae isolates, jeopardizing treatment options in the ICU, potentially increasing morbidity and mortality of critically ill patients and necessitating prudent use of colistin.

Journal ArticleDOI
TL;DR: It is shown that there is no simple relationship between increased knowledge and more prudent antibiotic use, and future national antibiotic campaigns should have a defined audience and aims in order to facilitate prudent antibiotics use by clinicians and public.
Abstract: Results: Although 79% of respondents were aware that ‘antibiotic resistance is a problem in British hospitals’, 38% of respondents did not know that antibiotics do not work against most coughs or colds and 43% did not know that ‘antibiotics can kill the bacteria that normally live on the skin and in the gut’. Respondents with lower educational qualifications were less knowledgeable about antibiotics. In a multivariable analysis, better knowledge of antibiotics was not associated with being less likely to be prescribed any in the last year, but was independently associated with being more likely to finish a course of antibiotic as prescribed. Knowledge was also associated with being more likely to take antibiotics without being told to do so. In women, better knowledge was associated with being more likely to give an antibiotic to someone else that was not prescribed for them.

Journal ArticleDOI
TL;DR: Adequate empirical therapy is used in a minority of patients with invasive Candida spp.
Abstract: Objectives: Although inadequate antimicrobial therapy has been demonstrated in multiple studies to increase the risk for death in bacterial infections, few data investigating the effect of antifungal therapy on outcome of serious fungal disease are available. We sought to assess the adequacy of empirical therapy and its effect on mortality in invasive Candida species infections. Methods: Population-based surveillance of all patients with Candida spp. cultured from blood and/or cerebrospinal fluid was conducted. Adequacy of empirical therapy was assessed according to published guidelines. Results: During a 5 year period, 207 patients had an invasive Candida spp. infection identified; in 199 cases (96%) adequate data were available for assessment of treatment and outcome at hospital discharge. One hundred and three (52%) cases were due to Candida albicans, 44 (22%) were due to Candida glabrata and the remainder were due to other species. Between the time of culture draw and reporting of a positive culture, only 64 (32%) patients were treated with empirical therapy; this was deemed adequate in 51 (26%). Patients who received adequate empirical therapy had a significant decrease in crude mortality [14/51 (27%) versus 68/148 (46%); risk ratio 0.60 (95% confidence interval 0.37‐0.96); P 5 0.02]. After adjusting for age and the need for intensive care unit admission in logistic regression analysis, the use of adequate empirical therapy was independently associated with a reduced risk for death [odds ratio 0.46 (95% confidence interval 0.22‐1.00); P 5 0.05]. Conclusions: Adequate empirical therapy is used in a minority of patients with invasive Candida spp. infections but is associated with improved survival.

Journal ArticleDOI
TL;DR: In this article, the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobial drugs are reviewed.
Abstract: There is growing universal concern regarding counterfeit medications. In particular, counterfeit antimicrobial drugs are a threat to public health with many devastating consequences for patients; increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating these patients lose their confidence in the medications used and report high levels of bacterial resistance. The problem with fake and suboptimal medications got worse with the advent of the World Wide Web; a significant proportion of medications that are sold through Internet pharmacies is counterfeit. Various initiatives of the WHO (the International Medical Products Anti-Counterfeiting Taskforce) are hopefully going to tackle this very important public health issue. In this article, we review the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobials.

Journal ArticleDOI
TL;DR: The data suggest that prior exposure to fluoroquinolones and antipseudomonal penicillins are independent risk factors for the development of CRKp infections.
Abstract: Results: One hundred and six patients were included in our study (53 cases and 53 controls). Mortality was 30.1% and 33.9% for patients with CRKp and CSKp infections, respectively (P 5 0.83). Bivariable analysis showed that exposure to anti-pseudomonas penicillins (P 5 0.004), carbapenems (P 5 0.01), quinolones (P < 0.001) and glycopeptides (P < 0.001), as well as admission to the intensive care unit (P 5 0.002), tracheostomy (P 5 0.02), chronic obstructive pulmonary disease (P 5 0.04), surgery with use of foreign body (P 5 0.04) and mechanical ventilation (P 5 0.02) were associated with CRKp infection. The multivariable analysis showed that exposure to fluoroquinolones [odds ratio (OR) 4.54, 95% confidence intervals (CIs) 1.78–11.54, P 5 0.001] and exposure to antipseudomonal penicillins (OR 2.57, 95% CI 1.00–6.71, P 5 0.04) were independent risk factors for CRKp infections.

Journal ArticleDOI
TL;DR: It is suggested that decreased susceptibility to tigecycline in the A. calcoaceticus-A.
Abstract: Received 25 October 2006; returned 5 December 2006; revised 21 December 2006; accepted 5 February 2007 Objectives: To investigate the role of the AdeABC multidrug efflux pump in the decreased susceptibility of clinical isolates of Acinetobacter calcoaceticus–Acinetobacter baumannii complex to tigecycline. Methods: Gene expression was analysed by Taqman RT-PCR. A single cross-over achieved insertional inactivation of the adeB gene with a suicide plasmid construct carrying an adeB fragment obtained by PCR. Analysis of the adeRS locus was performed by PCR and sequencing. Ribotyping was performed with the RiboPrinter system. MICs were determined by Etest. Results: Expression analysis revealed constitutive overexpression of adeABC in less-susceptible clinical isolates G5139 and G5140 (tigecycline MIC 5 4 mg/L) when compared with the isogenic clinical isolates G4904 and G5141 (MIC 5 1.5 mg/L). Insertional mutants GC7945 (adeB knockout in G5139) and GC7951 (adeB knockout in G5140) were obtained, which resulted in tigecycline MICs of 0.5 mg/L. As reported previously, the expression of adeABC is regulated by the two-component signalling system encoded by the adeR and adeS genes. PCR and sequencing analyses revealed an insertion of an ISABA-1 element in the adeS gene of G5139 and G5140. Conclusions: The results of this study suggest that decreased susceptibility to tigecycline in the A. calcoaceticus–A. baumannii complex is associated with the overexpression of the AdeABC multidrug efflux pump.

Journal ArticleDOI
TL;DR: The plasmid-encoded OqxAB pump has a wide substrate specificity and can be transferred between Enterobacteriaceae conferring reduced susceptibility to a multitude of substrates, which could indicate some dependence on the outer membrane proteins present in the different species.
Abstract: Objectives: A plasmid-encoded multidrug efflux pump, OqxAB, identified in Escherichia coli of porcine origin, was tested for substrate specificity against selected antibiotics, detergents and disinfectants. The ability of horizontal transfer to food-borne pathogens of the Enterobacteriaceae family was also investigated. Methods: The MICs of selected substrates were determined with a broth dilution assay using two isogenic E. coli strains, except for the presence of the oqxAB operon. A derivative of the plasmid encoding OqxAB (pOLA52) was constructed and horizontal transfer to Salmonella Typhimurium, Klebsiella pneumoniae, Kluyvera sp. and Enterobacter aerogenes was investigated. The effect of the presence of the OqxAB pump on susceptibility for selected compounds was investigated using broth dilution assays. Results: The OqxAB pump conferred antimicrobial resistance or reduced susceptibility towards a variety of substrates in E. coli. These included animal growth promoters, antimicrobials, disinfectants and detergents. pOLA52 could readily be transferred to enterobacterial pathogens. Transconjugants showed reduced susceptibility towards chloramphenicol, ciprofloxacin and olaquindox. Conclusions: The plasmid-encoded OqxAB pump has a wide substrate specificity and can be transferred between Enterobacteriaceae conferring reduced susceptibility to a multitude of substrates. These results could indicate some dependence on the outer membrane proteins present in the different species.

Journal ArticleDOI
TL;DR: Prophylactic intranasal mupirocin treatment of nasal S. aureus carriers before surgery results in a reduction of the post-operative S.Aureus infection rate.
Abstract: Objectives: The majority of nosocomial Staphylococcus aureus infections originate from the patients’ own flora, with nasal carriage of S. aureus before surgical procedures being a risk factor for subsequent infection. The objective of this review was to assess whether intranasal mupirocin treatment of nasal S. aureus carriers before surgery results in a reduction of the post-operative S. aureus infection rate. Methods: CENTRAL, EMBASE and MEDLINE were searched for the keywords mupirocin, pseudomonic acid or bactroban, combined with nasal or intranasal. Only randomized controlled studies investigating surgical patients were included. Titles and abstracts were screened independently by two reviewers. S. aureus infection data in nasal carriers with and without mupirocin treatment were pooled in the meta-analysis. Results: The literature search resulted in 211 hits, of which 4 articles met the inclusion criteria. Among the 686 mupirocin-treated surgical patients with S. aureus nasal carriage, there were 25 S. aureus infections (3.6%), compared with 46 (6.7%) in the controls (RR 0.55, 95% CI 0.34–0.89; P 5 0.02). Conclusions: Prophylactic intranasal mupirocin significantly reduced the rate of post-operative S. aureus infections among surgical patients who were S. aureus carriers.

Journal ArticleDOI
TL;DR: Future campaigns that are aimed at reducing the level of prescribing should be focused towards those more likely to be prescribed antibiotics at present: younger women and those with a lower level of education.
Abstract: Although a third of the public still believe that antibiotics work against coughs and colds, simply getting the public to believe otherwise may not be enough to reduce the level of prescribing. The large Department of Health sponsored household survey demonstrated that those with a greater knowledge about antibiotics were no less likely to be prescribed an antibiotic, and although those with increased knowledge about antibiotics were more likely to complete a course they were also more likely to self-medicate and to keep left-over antibiotics. Future campaigns that are aimed at reducing the level of prescribing should be focused towards those more likely to be prescribed antibiotics at present: younger women and those with a lower level of education. They should also examine and consider modifying consultation behaviour and other behavioural components involved in patient' expectations for antibiotics. This should include delayed antibiotic prescriptions. The easiest way to reduce the use of leftovers may be to shorten the course of antibiotics prescribed to 3 or 5 days. We should also promote a 'Do not recycle antibiotics' message towards the more highly educated, young women who are more likely to store, take and share antibiotics without advice.

Journal ArticleDOI
TL;DR: This paper expands the list of therapeutic or prophylactic antimicrobials potentially effective against B. cereus group isolates using two testing methods that produced comparable results.
Abstract: Results: Both methods yielded near-identical results at both temperatures for all antimicrobials except trimethoprim/sulfamethoxazole. Resistance to trimethoprim/sulfamethoxazole in 97% (92/95) was not always evident until tests were incubated for 48 h at 308C. All B. anthracis isolates were susceptible to 22 antimicrobials and resistant to trimethoprim/sulfamethoxazole while three isolates were erythromycin-intermediate. Whereas the B. thuringiensis were resistant to the b-lactams, two B. cereus, one B. mycoides ,fi veB. pseudomycoides and two B. mycoides/pseudomycoides were susceptible. Three B. cereus were solely clindamycin-resistant. Of the seven erythromycin-intermediate or -resistant B. cereus, three were resistant to clindamycin and one was resistant to clarithromycin and clindamycin. One B. mycoides was intermediately resistant to quinupristin/dalfopristin and meropenem and one was clindamycin-resistant. All B. pseudomycoides were clindamycin-resistant with one quinupristin/ dalfopristin-resistant. Two B. mycoides/pseudomycoides were intermediately resistant to quinupristin/ dalfopristin and clindamycin and a third was intermediately resistant to clindamycin alone. All isolates were susceptible to chloramphenicol, ciprofloxacin, gatifloxacin, gentamicin, levofloxacin, linezolid, moxifloxacin, rifampicin, streptomycin, tetracycline, tigecycline and vancomycin. Conclusions: This paper expands the list of therapeutic or prophylactic antimicrobials potentially effective against B. cereus group isolates using two testing methods that produced comparable results.

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TL;DR: This is the first controlled prospective ITS study to use feedback to reinforce antibiotic policy and reduce CDI and cluster randomized trials of this and other methods need to be undertaken to establish the most effective means of optimizing antibiotic use and reducing CDI.
Abstract: and feedback of antibiotic usage and CDI rates) was introduced, following an unplanned rise in amoxicillin/clavulanate (Augmentin) use. It targeted broad-spectrum antibiotics for reduction (cephalosporins and amoxicillin/clavulanate) and narrow-spectrum antibiotics for increase (benzyl penicillin, amoxicillin and trimethoprim). Changes in the use of targeted antibiotics (intervention group) were compared with those of untargeted antibiotics (control group) using segmented regression analysis. Changes in CDI rates were examined by the Poisson regression model. Methicillin-resistant Staphylococcus aureus (MRSA) acquisition rates acted as an additional control. Results: There was a reduction in the use of all targeted broad-spectrum antibiotics and an increase in all targeted narrow-spectrum antibiotics, statistically significant for sudden change and/or linear trend. All other antibiotic use remained unchanged. CDI rates fell with incidence rate ratios of 0.35 (0.17, 0.73) (P 5 0.009). MRSA incidence did not change [0.79 (0.49, 1.28); P 5 0.32].

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TL;DR: Tigecycline is a novel broad-spectrum antimicrobial that is active against the common organisms associated with infections and was the only antimicrobial to maintain activity against all Gram-positive isolates.
Abstract: OBJECTIVES To describe antimicrobial susceptibility among bacterial isolates associated with hospital infections collected from 266 centres in Asia/Pacific Rim (n = 1,947), North America (n = 24,283), Latin America (n = 1,957) and Europe (n = 8,796) METHODS Isolates were collected from blood, respiratory tract, urine, skin, wound, body fluids and other defined sources between January 2004 and August 2006 Only one isolate per patient was accepted In vitro MICs for the isolates were determined according to the CLSI (formerly NCCLS) guidelines RESULTS Key organisms collected were Acinetobacter baumannii (n = 2,902), Enterobacter spp (n = 5,731), Escherichia coli (n = 6,504), Klebsiella pneumoniae (n = 4,916), Pseudomonas aeruginosa (n = 5,128), Serratia marcescens (n = 2,313), Enterococcus faecalis (n = 2,701), Enterococcus faecium (n = 1,035) and Staphylococcus aureus (n = 5,753) Rates of methicillin resistance among S aureus and of vancomycin resistance among enterococci were highest in North America (2,016/3,809, 529% and 571/2,544, 224%, respectively) and lowest in Europe (337/1,340, 251% and 36/916, 39%, respectively) Tigecycline was the only antimicrobial to maintain activity against all Gram-positive isolates (MIC(90) values of 93% susceptibility in all regions) antimicrobials against the Gram-negative species, except for A baumannii and P aeruginosa Piperacillin/tazobactam and amikacin were the most active against P aeruginosa Extended-spectrum beta-lactamase producers among K pneumoniae occurred most frequently in Latin America (124/282, 440%) CONCLUSIONS Tigecycline is a novel broad-spectrum antimicrobial that is active against the common organisms associated with infections

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TL;DR: While rapid bacterial identification and susceptibility testing led to earlier changes and a significant reduction in antibiotic use, they did not reduce mortality.
Abstract: Introduction: Rapid bacterial identification and susceptibility tests can lead to earlier microbiological diagnosis and pathogen-directed, appropriate therapy. We studied whether accelerated diagnostics affected antibiotic use and patient outcomes. Patients and methods: A prospective randomized clinical trial was performed over a 2-year period. Inpatients were selected on the basis of a positive culture from normally sterile body fluids and randomly assigned to either a rapid intervention arm or the control arm. The intervention arm used the Vitek 2 automated identification and susceptibility testing device, combined with direct inoculation of blood cultures. In the control arm, the Vitek 1 system inoculated from subcultures was used. Follow-up was 4 weeks after randomization. Results: A total of 1498 patients were randomized: 746 in the intervention arm and 752 in the control arm. For susceptibility testing, the rapid arm was 22 h faster than the control arm, and for identification, it was 13 h faster (P < 0.0001). In the rapid arm, antibiotic use was 6 defined daily doses lower per patient than in the control arm (P = 0.012). Whereas antibiotics were switched more in the rapid group on the day of randomization (P = 0.006), in the control group they were switched more on day two (P = 0.02). Mortality rates did not differ significantly between the two groups (17.6% versus 15.2%). Conclusions: While rapid bacterial identification and susceptibility testing led to earlier changes and a significant reduction in antibiotic use, they did not reduce mortality.

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TL;DR: Inadequate antimicrobial therapy at admission to the ICU with sepsis is associated with excess mortality and increases LOS, and a significant increment in duration of hospitalization in surviving pairs.
Abstract: Objectives: To determine the attributable mortality and excess length of stay (LOS) associated with the use of inadequate empirical antimicrobial therapy in patients with sepsis at admission to the intensive care unit (ICU). Methods: A retrospective matched cohort study was performed using a prospectively collected database at a 40 bed general ICU at a university public hospital. Patients who received inadequate antimicrobial therapy at admission to the ICU (exposed) were matched with controls (unexposed) on the basis of origin of sepsis, inflammatory response at admission, surgical or medical status, hospital- or community-acquired sepsis, APACHE II score (+ +2 points) and age (+ +10 years). Clinical outcome was assessed by in-hospital mortality, and this analysis was also performed in those pairs without nosocomial infection in the ICU. Results: Eighty-seven pairs were successfully matched. Fifty-nine exposed patients died [67.8% mortality (95% CI, 58.0‐77.6%)] and 25 unexposed controls died [28.7% mortality (95% CI, 19.2‐ 38.2%)] (P < 0.001). Excess in-hospital mortality was estimated to be 39.1%. The rate of nosocomial infection was significantly higher in patients with inadequate empirical therapy (16.1%) than in those treated empirically with adequate antibiotics (3.4%) (P 5 0.013). Excess in-hospital mortality was 31.4% after excluding those 17 pairs that developed a nosocomial infection in the ICU. Inadequate antimicrobial therapy was associated with a significant increment in duration of hospitalization (15 days in surviving pairs). Conclusions: Inadequate antimicrobial therapy at admission to the ICU with sepsis is associated with excess mortality and increases LOS.