Showing papers in "Journal of Antimicrobial Chemotherapy in 2009"
TL;DR: Some of the new mechanisms and recent trends in the global spread of multidrug resistant (MDR) bacteria are reviewed, with the emergence of community-associated methicillin-resistant Staphylococcus aureus blurring the distinction between hospital and community strains.
Abstract: Antibiotic resistance is now a linked global problem. Dispersion of successful clones of multidrug resistant (MDR) bacteria is common, often via the movement of people. Local evolution of MDR bacteria is also important under the pressure of excessive antibiotic use, with horizontal gene transfer providing the means by which genes such as bla(CTX-M) spread amongst different bacterial species and strains. Beta-lactamase production is a common resistance mechanism in Gram-negative bacteria, and the rapid dissemination of novel genes reflects their evolution under the selective pressure of antibiotic usage. Many Enterobacteriaceae now carry broad-spectrum beta-lactamases such as CTX-M, with particular genotypes associated with different geographical regions. The spread of these enzymes has compromised the clinical utility of a number of beta-lactam classes and with the spread of genes such as bla(KPC), carbapenems may be increasingly compromised in the future. High-level fluoroquinolone resistance (mainly caused by gyrA mutations) has also been shown to be associated with CTX-M and CMY-type enzymes, commonly due to co-carriage on conjugative plasmids of the gene for the aminoglycoside-inactivating enzyme AAC-6(1)-Ib-cr and qnr genes (which confer low-level resistance), allowing the easy selection of gyrA mutants in the host strain. Resistance in Gram-positive bacteria is also widely distributed and increasing, with the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) blurring the distinction between hospital and community strains. Antibiotic use and environmental factors all have a role in the emergence and spread of resistance. This article reviews some of the new mechanisms and recent trends in the global spread of MDR bacteria.
769 citations
TL;DR: No agent in advanced development has much to offer here, though there is interest in modified, less-toxic, polymyxin derivatives and in the siderophore monobactam BAL30072, which has impressive activity against A. baumannii and members of the Burkholderia cepacia complex.
Abstract: Antibiotic resistance is a major public health concern, with fears expressed that we shortly will run out of antibiotics. In reality, the picture is more mixed, improving against some pathogens but worsening against others. Against methicillin-resistant Staphylococcus aureus (MRSA)--the highest profile pathogen--the range of treatment options is expanding, with daptomycin, linezolid and tigecycline all launched, and telavancin, ceftobiprole, ceftaroline and dalbavancin anticipated. There is a greater problem with enterococci, especially if, as in endocarditis, bactericidal activity is needed and the isolate has high-level aminoglycoside resistance; nevertheless, daptomycin, telavancin and razupenem all offer cidal potential. Against Enterobacteriaceae, the rapid and disturbing spread of extended-spectrum beta-lactamases, AmpC enzymes and quinolone resistance is forcing increased reliance on carbapenems, with resistance to these slowly accumulating via the spread of metallo-, KPC and OXA-48 beta-lactamases. Future options overcoming some of these mechanisms include various novel beta-lactamase-inhibitor combinations, but none of these overcomes all the carbapenemase types now circulating. Multiresistance that includes carbapenems is much commoner in non-fermenters than in the Enterobacteriaceae, depending mostly on OXA carbapenemases in Acinetobacter baumannii and on combinations of chromosomal mutation in Pseudomonas aeruginosa. No agent in advanced development has much to offer here, though there is interest in modified, less-toxic, polymyxin derivatives and in the siderophore monobactam BAL30072, which has impressive activity against A. baumannii and members of the Burkholderia cepacia complex. A final and surprising problem is Neisseria gonorrhoeae, where each good oral agent has been eroded in turn and where there is now little in reserve behind the oral oxyimino cephalosporins, to which low-level resistance is emerging.
597 citations
TL;DR: Although predominantly a cause of skin and soft issue infection, MRSA USA300 isolates also have been recovered from cases of invasive disease including bacteraemia, endocarditis, severe necrotizing pneumonia and osteomyelitis, and have spread to Europe, South America and Australia.
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) PFGE strain type USA300 (multilocus sequence type 8, clonal complex 8, staphylococcal cassette chromosome mec type IV) was first reported in the USA as a cause of skin and soft issue infection among college football players in Pennsylvania and among prisoners in Missouri in 2000. Over the next 5 years, USA300 became the predominant community-associated MRSA strain in the USA. It was the most common PFGE type recovered from skin and soft tissue infections in persons presenting to 11 emergency departments across the USA, and caused outbreaks in Native American populations, children in daycare centres, military recruits, prison inmates and among men who have sex with men. Although predominantly a cause of skin and soft issue infection, USA300 isolates also have been recovered from cases of invasive disease including bacteraemia, endocarditis, severe necrotizing pneumonia and osteomyelitis. Isolates of USA300 usually carry the genes encoding the Panton-Valentine leucocidin and the arginine catabolic mobile element, but rarely carry staphylococcal enterotoxin genes. USA300 isolates are becoming more resistant to antimicrobial agents, including erythromycin, levofloxacin, mupirocin and tetracycline, and have spread to Europe, South America and Australia. The emergence of the MRSA USA300 strain type represents a unique biological success story.
421 citations
TL;DR: Ertapenem resistance was exclusively due to combinations of beta-lactamases with impermeability caused by loss of OMPs, and there was no evidence of efflux contributing to resistance.
Abstract: Objectives The aim of this study was to investigate relatedness and molecular mechanism(s) of ertapenem resistance in clinical isolates of Klebsiella spp. (n?=?28) and Enterobacter spp. (n?=?27) referred from multiple hospitals to the UK national reference laboratory. Methods Investigations included genotyping by PFGE, resistance gene analysis by PCR and antimicrobial susceptibility testing with and without inhibitors of efflux and s-lactamase activity. Outer membrane proteins (OMPs) were profiled by SDS–PAGE; porin genes were sequenced and their expression was examined by RT–PCR. The contribution of porin deficiency to resistance was investigated by restoring functional porin genes on plasmids. Results PFGE showed significant clonal diversity among ertapenem-resistant isolates, with only small clusters identified. SHV- and CTX-M-type extended-spectrum s-lactamases were identified in the Klebsiella spp. isolates, whereas AmpC overexpression or KPC carbapenemase was detected in the Enterobacter cloacae isolates. SDS–PAGE showed that Klebsiella pneumoniae and Enterobacter aerogenes with high-level ertapenem resistance (MICs?=?16 mg/L) consistently lacked both of the two major non-specific porins, whereas variable patterns of OmpC and OmpF were seen in E. cloacae with lower-level ertapenem resistance. Various point mutations or insertion sequences were identified as disrupting the porin-coding sequences, as well as mutations in the promoter region. Functional restoration of OmpK35 or OmpK36 in Klebsiella and OmpC or OmpF in Enterobacter spp. isolates significantly decreased the MICs of all carbapenems, but particularly of ertapenem. We found no evidence of efflux contributing to resistance. Conclusions Ertapenem resistance was exclusively due to combinations of s-lactamases with impermeability caused by loss of OMPs. Efflux was not implicated and there was no national spread of resistant clones.
406 citations
TL;DR: A PCR-based assay is developed that easily identifies a clone with high likelihood of producing ESBLs, including CTX-M-15, which represents 3% of non-ESBL B2 isolates originating from urinary tract infections in Paris.
Abstract: Objectives Recently, a CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli O25b-ST131 clone, belonging to the B2 phylogenetic group and with a high virulence potential, has been reported all over the world, representing a major public health problem. The present study was carried out to develop a rapid and simple detection assay that identifies members of this clone. Methods A total of 627 E. coli isolates of which 373 produced an ESBL, collected across four continents, were screened using a O25b-ST131 clone allele-specific PCR for the pabB gene. Results One hundred and forty-three ESBL isolates were found positive with the assay. These isolates were all of O25b type and, when studied by multilocus sequence typing (25 cases), were all of ST131. The O25b-ST131 clone was found to produce ESBLs other than CTX-M-15, specifically CTX-M-2, -3, -14, -27, -32 and -61 as well as TEM-24. This clone represents 3% of non-ESBL B2 isolates originating from urinary tract infections in Paris. Conclusions We have developed a PCR-based assay that easily identifies a clone with high likelihood of producing ESBLs, including CTX-M-15.
359 citations
TL;DR: Treatment failure rates by antibiotic duration for prosthetic joint infection managed with debridement, antibiotics and implant retention (DAIR) are described and PJI may be managed by DAIR.
Abstract: Results: One hundred and twelve cases of PJI were identified. Twenty infections (18%) recurred during a mean follow-up of 2.3 years. The mean duration of antibiotic use was 1.5 years. Failure was more common after arthroscopic debridement, for previously revised joints and for Staphylococcus aureus infection. There were 12 failures after stopping antibiotics and 8 while on antibiotics [hazard ratio (HR) 54.3, 95% confidence interval (CI) 1.4‐12.8, P 50.01]. However, during the first 3 months of follow-up, there were eight failures after stopping antibiotics and two while on antibiotics (HR 57.0, 95% CI 1.5‐33, P 50.015). The duration of antibiotic therapy prior to stopping did not predict outcome. Conclusions: PJI may be managed by DAIR. The risk of failure with this strategy rises after stopping oral antibiotics, but lengthening antibiotic therapy may simply postpone, rather than prevent, failure.
308 citations
TL;DR: It was found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing, and administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.
Abstract: Objectives: To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units.
305 citations
TL;DR: Chlorhexidine digluconate may be combined with either crude EO or its major component 1,8-cineole for enhanced, synergistic antimicrobial activity against a wide range of microorganisms in planktonic and biofilm modes of growth.
Abstract: Received 11 August 2009; returned 7 September 2009; revised 11 September 2009; accepted 12 September 2009 Objectives: Effective disinfection and antisepsis is pivotal in preventing infections within the healthcare setting. Chlorhexidine digluconate (CHG) is a widely used disinfectant/antiseptic possessing broad-spectrum antimicrobial activity; however, its penetration into bacterial biofilms and human skin is poor. The aim of this study was to investigate the antimicrobial efficacy of crude eucalyptus oil (EO) and its main component 1,8-cineole (a recognized permeation enhancer), alone and in combination with CHG, against a panel of clinically relevant microorganisms grown in planktonic and biofilm cultures. Methods: MICs and minimum bactericidal/fungicidal concentrations were determined for each microorganism grown in suspension and biofilm using microbroth dilution and ATP bioluminescence, respectively. Chequerboard assays were used to determine synergistic, indifferent or antagonistic interactions between CHG and EO or 1,8-cineole. Results: Antimicrobial activity was demonstrated by CHG, EO and 1,8-cineole; however, CHG was significantly more active against microorganisms in both planktonic and biofilm modes of growth (P<0.05). Crude EO was significantly more efficacious against microorganisms grown in suspension compared with 1,8-cineole (P<0.05). Synergistic activity was demonstrated between CHG and both EO and 1,8-cineole against suspensions of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Escherichia coli and Candida albicans, and biofilm cultures of MRSA and Pseudomonas aeruginosa. Conclusions: In conclusion, CHG may be combined with either crude EO or its major component 1,8cineole for enhanced, synergistic antimicrobial activity against a wide range of microorganisms in planktonic and biofilm modes of growth; however, the superior antimicrobial efficacy associated with crude EO alone, compared with 1,8-cineole, favours its combination with CHG.
257 citations
TL;DR: Multiple events of mobilization, transposition and replicon fusion generate the complexity observed in qnr-positive isolates that are emerging worldwide.
Abstract: Objectives: The aim of this study was to identify and characterize plasmids carrying qnrS1, qnrB2 and qnrB19 genes identified in Salmonella strains from The Netherlands. The identification of plasmids may help to follow the dissemination of these resistance genes in different countries and environments. Methods: Plasmids from 33 qnr-positive Salmonella strains were transferred to Escherichia coli and analysed by restriction, Southern blot hybridization, PCR and sequencing of resistance determinants. They were also assigned to incompatibility groups by PCR-based replicon typing, including three additional PCR assays for the IncU, IncR and ColE groups. The collection included isolates from humans and one from chicken meat. Results: Five IncN plasmids carrying qnrS1, qnrB2 and qnrB19 genes were identified in Salmonella enterica Bredeney, Typhimurium PT507, Kentucky and Saintpaul. qnrS1 genes were also located on three further plasmid types, belonging to the ColE (in Salmonella Corvallis and Anatum), IncR (in Salmonella Montevideo) and IncHI2 (in Salmonella Stanley) groups. Conclusions: Multiple events of mobilization, transposition and replicon fusion generate the complexity observed in qnr-positive isolates that are emerging worldwide. Despite the fact that the occurrence of qnr genes in bacteria from animals is scarcely reported, these genes are associated with genetic elements and located on plasmids that are recurrent in animal isolates.
252 citations
TL;DR: With parameters in the range estimated, the mathematical model predicts that the course of antibiotic treatment can be affected by cell density; treatment protocols based on conventional (density-independent) MICs can fail to clear higher density infections.
Abstract: Results: Modest or substantial inoculum effects on efficacy were observed for all six antibiotics studied, such as density-dependent declines in the rate and extent of antibiotic-mediated killing and increases in MIC. Although these measures of antibiotic efficacy declined with inoculum, this density effect did not increase monotonically. At higher densities, the rate of kill of ciprofloxacin and oxacillin declined with the antibiotic concentration. For daptomycin and vancomycin, much of this inoculum effect is due to density-dependent reductions in the effective concentration of the antibiotic. For the other four antibiotics, this density effect is primarily associated with a decrease in per-cell antibiotic concentration. With parameters in the range estimated, our mathematical model predicts that the course of antibiotic treatment can be affected by cell density; treatment protocols based on conventional (density-independent) MICs can fail to clear higher density infections. Conclusions: The MICs used for pharmacokinetic/pharmacodynamic indices should be functions of the anticipated densities of the infecting population.
230 citations
TL;DR: The 2008 WHO N. gonorrhoeae reference strain panel was extensively characterized to allow valid comparison of AMR data derived by divergent methods, and also for the control of present and future molecular assays for AMR detection.
Abstract: Objectives: Emergence and spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae remain a major global problem and expanded, but valid, AMR surveillance is crucial for public health purposes. The World Health Organization (WHO) Collaborating Centre in Sydney, Australia, continually evaluates N. gonorrhoeae strains used in quality control and assurance aspects of the national, WHO regional and international programmes for AMR surveillance it conducts. Here we phenotypically and genetically characterized the 2008 WHO N. gonorrhoeae reference panel, widely used under existing WHO AMR surveillance protocols. Materials and methods: The eight N. gonorrhoeae WHO reference strains were phenotypically characterized by antibiogram, auxotype, serovar and prolyliminopeptidase screening; and genetically with regard to resistance plasmid types, polymorphisms in divergent genetic resistance-mediating loci (n 59), porB sequencing and N. gonorrhoeae multi-antigen sequence typing. Results: The 2008 WHO reference strains represented all the important susceptible and resistant phenotypes, including corresponding resistance genotypes, and the range of resistances currently seen for relevant antimicrobials. Several pertinent additional phenotypic and genotypic markers, for example, epidemiological markers, were also determined. Conclusions: The 2008 WHO N. gonorrhoeae reference strain panel was extensively characterized, which is crucial for the expansion of gonococcal AMR surveillance nationally and internationally. The panel is available through WHO sources for quality assurance and quality control aspects of current phenotypic testing protocols, to allow valid comparison of AMR data derived by divergent methods, and also for the control of present and future molecular assays for AMR detection. Additional WHO reference strains can be included as required by the emergence of additional resistant phenotypes and/or genotypes.
TL;DR: The complex beta-lactamase background of KPC-Kp isolates that are emerging in multiple centres in the Eastern USA demonstrated the prevalence of a single dominant clone suggests that interstate transmission has occurred.
Abstract: Background
The emergence of blaKPC-containing Klebsiella pneumoniae (KPC-Kp) isolates is attracting significant attention. Outbreaks in the Eastern USA have created serious treatment and infection control problems. A comparative multi-institutional analysis of these strains has not yet been performed.
TL;DR: Using this service model, OPAT is safe and clinically effective, with low rates of complications/readmissions and high levels of patient satisfaction, and is cost-effective when compared with equivalent inpatient care in the UK healthcare setting.
Abstract: Objectives: Outpatient parenteral antibiotic therapy (OPAT) is an effective treatment strategy for a wide variety of infections as long as clinical risk is minimized by conforming to practice guidelines. However, its cost-effectiveness has not been established in the setting of the UK National Health Service. We examined the clinical efficacy and cost-effectiveness of an OPAT service based in a large UK teaching hospital, predominantly using the outpatient ‘infusion centre’ and patient/carer administration models of service delivery. Patients and methods: Data on clinical activity and outcomes were collected prospectively on 334 episodes of treatment administered by the Sheffield OPAT service between January 2006 and January 2008. Cost-effectiveness was calculated by comparing real costs of OPAT with estimated inpatient costs for these patient episodes incorporating two additional sensitivity analyses. Results: Of the OPAT episodes, 87% resulted in cure or improvement on completion of intravenous therapy. The readmission rate was 6.3%, and patient satisfaction was high. OPAT cost 41% of equivalent inpatient costs for an Infectious Diseases Unit, 47% of equivalent inpatient costs using national average costs and 61% of inpatient costs using minimum inpatient costs for each diagnosis. Conclusions: Using this service model, OPAT is safe and clinically effective, with low rates of complications/readmissions and high levels of patient satisfaction. OPAT is cost-effective when compared with equivalent inpatient care in the UK healthcare setting.
TL;DR: The high level of faecal carriage of MDR E. coli in nursing home residents demonstrates their importance as a reservoir population and public health measures to combat spread of these organisms should address the needs of this group.
Abstract: BACKGROUND: To assess the prevalence and risk factors for faecal carriage of fluoroquinolone-resistant, extended-spectrum beta-lactamase (ESBL)-producing, Escherichia coli (MDR E. coli) among residents in nursing homes in Northern Ireland. METHODS: Between January 2004 and May 2006, retrospective histories of hospital admissions, antimicrobial treatment and co-morbidities were collected. Faecal samples were cultured for MDR E. coli. These isolates and their ESBL genes were typed by a reference laboratory. RESULTS: Of the 294 patients included in the study, faecal samples from 119 (40.5%) grew MDR E. coli. The proportion of carriers in the different homes ranged from 0% to 75%. Epidemic strain A belonging to the ST131, O25:H4 lineage with the CTX-M-15 enzyme accounted for 58 (49%) of all isolates; its proportion varied from 0% to 100% among homes. Fifty-one percent of carriers had no history of recent hospital admission and only 13.5% had a known history of ESBL E. coli colonization or infection. In a multivariate logistic regression model, days of fluoroquinolone use [odds ratio (OR) = 1.33, 95% confidence interval (CI) 1.04-1.69, P = 0.02] and a history of urinary tract infection (OR = 2.56, 95% CI 1.37-4.78, P = 0.003) were the only variables independently associated with the risk of carrying MDR E. coli. CONCLUSIONS: The high level of faecal carriage of MDR E. coli in nursing home residents demonstrates their importance as a reservoir population. Public health measures to combat spread of these organisms should address the needs of this group.
TL;DR: MRSA from Chinese pigs and farm workers (ST9) differed from the European pig-associated clone (ST398) with regard to clonal type, SCCmec content and resistance profile.
Abstract: Objectives The objectives of this study were to determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization in livestock and related workers in four Chinese provinces and the characteristics of these isolates. Methods Nasal swabs were collected from animals and farm workers in four Chinese provinces. MRSA isolates were recovered and characterized by PFGE, Panton-Valentine leucocidin PCR, staphylococcal chromosomal cassette (SCC) mec typing, spa typing, multilocus sequence typing, antimicrobial susceptibility testing and testing for inducible clindamycin resistance. Results A total of 60 MRSA isolates were recovered from swine and swine workers. Two predominant multidrug resistance profiles were identified: ciprofloxacin/clindamycin/erythromycin/cefoxitin/gentamicin/tetracycline/chloramphenicol and ciprofloxacin/clindamycin/erythromycin/cefoxitin/gentamicin/tetracycline. All isolates were determined to be spa type t899, contained the group III SCCmec element and were Panton-Valentine leucocidin negative. Multilocus sequence type ST9 (n = 46) was identified as the dominant sequence type. One dominant PFGE cluster and a dominant strain type were identified. Conclusions MRSA from Chinese pigs and farm workers (ST9) differed from the European pig-associated clone (ST398) with regard to clonal type, SCCmec content and resistance profile.
TL;DR: The combination of triclosan and DspB showed synergistic antimicrobial and antibiofilm activity against S. aureus, significantly reduced bacterial colonization and generally demonstrated a prolonged superior antimicrobial activity against clinical pathogens compared with CH-SS-coated catheters.
Abstract: Objectives: The objectives of this study were to examine: (i) synergy of the combination of triclosan and DispersinB ® (DspB); (ii) in vitro efficacy and durability of triclosan + DspB-coated vascular catheters ; and (iii) in vivo efficacy of triclosan + DspB-coated catheters compared with chiorhexidine-silver sulfadiazine (CH-SS)-coated and uncoated (control) vascular catheters in preventing colonization by Staphylococcus aureus. Methods: We investigated the potential synergistic antimicrobial and antibiofilm activity of triclosan and DspB by biofilm assays. The in vitro antimicrobial efficacy of triclosan + DspB-coated catheters was determined by microbial colonization assays. Antimicrobial durability of the coated catheters was tested by soaking segments in bovine serum for 7 days and determining antimicrobial activity, and by a serial plate transfer method. The in vivo efficacy of triclosan + DspB-coated catheters compared with CH-SS-coated and uncoated catheters was assessed by subcutaneous implantation of segments in a rabbit model of S. aureus infection. Results: The combination of triclosan and DspB showed synergistic antimicrobial and antibiofilm activity against S. aureus, Staphylococcus epidermidis and Escherichia coli, significantly reduced bacterial colonization (P<0.05) and generally demonstrated a prolonged superior antimicrobial activity against clinical pathogens compared with CH-SS-coated catheters. Triclosan + DspB-coated and CH-SS-coated catheters exhibited equal in vivo efficacy (P<0.05) in reducing colonization by S. aureus compared with uncoated catheters. Conclusions: Catheters coated with the triclosan + DspB combination showed synergistic, broad-spectrum and durable antimicrobial activity. Furthermore, the in vivo efficacy of catheters coated with this unique antimicrobial/antibiofilm composition prompts clinical evaluation of such an innovative approach.
TL;DR: NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum β-lactamases, class C enzymes and class A carbapenemases, and given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, it is a promising agent to be used in combination with a β- lactam to protect its antibacterial activity.
Abstract: Background: NXL104 is a novel-structure b-lactamase inhibitor with potent activity against both class A and class C enzymes. Among the class A carbapenemases, KPC-type enzymes are now spreading rapidly and KPC-related carbapenemase resistance is an emerging phenomenon of great clinical importance. The activity of NXL104 against KPC b-lactamases was examined. Methods: Enzymatic activity of purified recombinant KPC-2 was measured with nitrocefin as reporter substrate and inhibition by NXL104 was measured by determination of IC50 values. Antimicrobial susceptibility testing of various b-lactams combined with a fixed concentration of NXL104 at 4 mg/L against strains producing KPC enzymes was performed by the broth microdilution method. Results: NXL104 was a potent inhibitor of KPC-2 with an IC50 of 38 nM. NXL104 restored the antimicrobial activity of ceftazidime, ceftriaxone, imipenem and piperacillin against Enterobacteriaceae strains producing KPC-2 or KPC-3. MIC values of ceftazidime against KPC producers were reduced by up to 1000-fold by combination with NXL104. Conclusions: NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum b-lactamases, class C enzymes and class A carbapenemases. Given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, NXL104 b-lactamase inhibitor is a promising agent to be used in combination with a b-lactam to protect its antibacterial activity.
TL;DR: There is no convincing evidence that mupirocin treatment reduces the incidence of surgical site infection, and new antibiotics are needed to decolonize the nose because bacterial resistance to m upirocin is rising, and so it will become less effective.
Abstract: Staphylococcus aureus in the nose is a risk factor for endogenous staphylococcal infection. UK guidelines recommend the use of mupirocin for nasal decolonization in certain groups of patients colonized with methicillin-resistant S. aureus (MRSA). Mupirocin is effective at removing S. aureus from the nose over a few weeks, but relapses are common within several months. There are only a few prospective randomized clinical trials that have been completed with sufficient patients, but those that have been reported suggest that clearance of S. aureus from the nose is beneficial in some patient groups for the reduction in the incidence of nosocomial infections. There is no convincing evidence that mupirocin treatment reduces the incidence of surgical site infection. New antibiotics are needed to decolonize the nose because bacterial resistance to mupirocin is rising, and so it will become less effective. Furthermore, a more bactericidal antibiotic than mupirocin is needed, on the grounds that it might reduce the relapse rate, and so clear the patient of MRSA for a longer period of time than mupirocin.
TL;DR: Inappropriate empirical therapy was the strongest independent factor that the authors could modify to improve mortality in E. coli bacteraemia and was more frequent in cases caused by fluoroquinolone-resistant or ESBL-producing strains.
Abstract: Results: Out of 18080 episodes, 4758 (26%) E. coli bacteraemias were reported in the period of study. Mortality was noted in 440 cases (9%). Fluoroquinolone-resistant strains were reported in 1300 (27%) cases and ESBL-producing strains in 211 cases (4%). One hundred and seventy-eight strains out of 211 (84%) ESBL-producing E. coli were isolated since 2001. The two main independent risk factors for mortality were shock (OR: 10.28, P<0.001) and inappropriate empirical therapy (OR: 4.83, P<0.001). Inappropriate empirical therapy was significantly more frequent for infections caused by fluoroquinolone-resistant strains (n 5203, 16%, P<0.001) and ESBL-producing strains (n 5110, 52%, P<0.001). Independent factors associated with the isolation of a fluoroquinolone-resistant strain were: nosocomial origin (OR: 1.61, P<0.001); urinary catheterization (OR: 2.44, P<0.001); and previous therapy with a fluoroquinolone (OR: 7.41, P<0.001). The independent risk factors associated with the isolation of an ESBL-producing strain were: nosocomial origin (OR: 1.68, P 50.03); urinary catheterization (OR: 1.88, P 50.001); and previous b-lactam antibiotic therapy (OR: 2.81, P<0.001). Conclusions: Inappropriate empirical therapy was the strongest independent factor that we could modify to improve mortality in E. coli bacteraemia and was more frequent in cases caused by fluoroquinoloneresistant or ESBL-producing strains. Nosocomial acquisition, urinary catheterization and previous therapy with a fluoroquinolone or b-lactam were predictive factors for infection with an antibioticresistant strain.
TL;DR: The emergence of KPC-producing isolates of K. pneumoniae in Norway and Sweden is associated with multiple import events and probable local transmission of a successful multiresistant ST258 clone, closely related to the CTX-M-15-producing ST11 clone previously described in Hungary.
Abstract: Background The class A carbapenemase KPC has disseminated rapidly worldwide, challenging the treatment of Gram-negative infections. This report describes the first KPC-producing Klebsiella pneumoniae isolates identified in Norway (n=6) and the second isolate from Sweden. Methods Antimicrobial susceptibility profiles were determined using Etest. PCR and sequencing were used to determine the bla(KPC) variant, the surrounding genetic structure and the presence of AmpC and extended-spectrum beta-lactamase genes. PFGE and multilocus sequence typing (MLST) were used for epidemiological comparisons. Localization of bla(KPC) was investigated by S1 nuclease digestion, followed by PFGE and Southern blot hybridization. Results All isolates expressed a multidrug-resistant phenotype with some variability in the carbapenem susceptibility profile. The Norwegian isolates carried bla(KPC-2), while the Swedish isolate carried bla(KPC-3). All isolates carried TEM-1, but were negative for bla(CTX-M) and bla(AmpC) genes. SHV-11 and SHV-12 were detected in the Norwegian isolates, while the Swedish isolate carried only SHV-11. Isolates from four patients were associated with import from Greece (n=3) and Israel. The other isolates were probably associated with local transmissions. PFGE and MLST showed that the isolates were clonally related, with three isolates displaying ST258, a single locus variant of ST11 previously associated with the clonal spread of CTX-M-15-producing K. pneumoniae in Hungary. In all isolates, bla(KPC) was located on plasmids as part of isoform a of Tn4401. Conclusions The emergence of KPC-producing isolates of K. pneumoniae in Norway and Sweden is associated with multiple import events and probable local transmission of a successful multiresistant ST258 clone, closely related to the CTX-M-15-producing ST11 clone previously described in Hungary.
TL;DR: The anti-PcrV immunoglobulin G antibody that blocks the type III secretion system-mediated virulence of P. aeruginosa has recently entered Phase I/II clinical trials, and Experimental polypeptides may provide a new therapeutic approach.
Abstract: Pseudomonas aeruginosa is an important cause of nosocomial pneumonia associated with a high morbidity and mortality rate. This bacterium expresses a variety of factors that confer resistance to a broad array of antimicrobial agents. Empirical antibiotic therapy is often inadequate because cultures from initial specimens grow strains that are resistant to initial antibiotics. Surveillance data, hospital antibiogram and individualization of regimens based on prior antibiotic use may reduce the risk of inadequate therapy. The use of combination therapies for P. aeruginosa pneumonia has been a long-advocated practice, but the potential increased value of combination therapy over monotherapy remains controversial. Doripenem and biapenem are new carbapenems that have excellent activity against P. aeruginosa; however, they lack activity against strains that express resistance to the currently available carbapenems. The polymyxins remain the most consistently effective agents against multidrug-resistant P. aeruginosa. Strains that are panantibiotic-resistant are rare, but their incidence is increasing. Antibiotic combinations that yield some degree of susceptibility in vitro are the recourse, although the efficacy of these regimens has yet to be established in clinical studies. Experimental polypeptides may provide a new therapeutic approach. Among these, the anti-PcrV immunoglobulin G antibody that blocks the type III secretion system-mediated virulence of P. aeruginosa has recently entered Phase I/II clinical trials.
TL;DR: Analysis of available information reveals that the efficacy of treatment in late chronic infection is doubtful, and data generally point to a beneficial effect, but this could be marginal.
Abstract: Background and objectives: The recent significant increase in the number of immigrants entering the European Union from South and Central America means that chronic Chagas' disease is an increasingly frequent diagnosis among immigrants in Europe. Our objectives were to evaluate published evidence on the treatment of chronic Chagas' disease with benznidazole and on the potential benefits of this drug in the chronic phase of the disease. Methods: We performed a systematic review and meta-analysis by means of an electronic search of the published literature, with no language restrictions, until October 2008. We included studies on chronically infected patients of any age who were in the indeterminate phase or had visceral involvement and for whom treatment with benznidazole was compared with placebo or no treatment. The primary endpoint was response to therapy (whether serological, parasitological or clinical), as it was measured in each of the studies included. Clinical response to therapy was also analysed. Results: We identified 696 studies, from which we chose 9: 3 clinical trials and 6 observational studies. Compared with placebo or no treatment, benznidazole increases 18-fold the probability of a response to therapy [global odds ratio (OR), 18.8; 95% confidence interval (CI), 5.2-68.3]. This effect was mainly observed in clinical trials (OR, 70.8; 95% CI, 16-314), whereas in observational studies it was much less marked (OR, 7.8; 95% CI, 2.1-28.9), and even less so when only observational studies in adults were considered (OR, 6.3; 95% CI, 1.6-24.7). Patients treated with benznidazole had a significantly lower risk of clinical events (OR, 0.29; 95% CI, 0.16-0.53). Up to 18% of patients discontinued treatment due to toxicity (cutaneous reactions followed by gastrointestinal disturbances); this was less common in children than in adults. Conclusions: Analysis of available information reveals that the efficacy of treatment in late chronic infection is doubtful. Although data generally point to a beneficial effect, this could be marginal. This uncertainty is largely the result of differences in the study populations, endpoints and follow-up periods, and the fact that almost all of the information on treatment in the late chronic phase comes from non-randomized studies.
TL;DR: There is a higher diversity of microorganisms isolated in nosocomial infections and decreased susceptibility among these strains, and the adequacy of treatment is comparable in the two groups.
Abstract: OBJECTIVES The EBIIA (Etude epidemiologique Bacterio-clinique des Infections Intra-Abdominales) study was designed to describe the clinical, microbiological and resistance profiles of community-acquired and nosocomial intra-abdominal infections (IAIs). PATIENTS AND METHODS From January to July 2005, patients undergoing surgery/interventional drainage for IAIs with a positive microbiological culture were included by 25 French centres. The primary endpoint was the epidemiology of the microorganisms and their resistance to antibiotics. Multivariate analysis was carried out using stepwise logistic regression to assess the factors predictive of death during hospitalization. RESULTS Three hundred and thirty-one patients (234 community-acquired and 97 nosocomial) were included. The distribution of the microorganisms differed according to the type of infection. Carbapenems and amikacin were the most active agents in vitro against Enterobacteriaceae in both community-acquired and nosocomial infections. Against Pseudomonas aeruginosa, amikacin, imipenem, ceftazidime and ciprofloxacin were the most active agents in community-acquired infections, while imipenem, cefepime and amikacin were the most active in nosocomial cases. Against the Gram-positive bacteria, vancomycin and teicoplanin were the most active in both infections. Against anaerobic bacteria, the most active agents were metronidazole and carbapenems in both groups. Empirical antibiotic therapy adequately targeted the pathogens for 63% of community-acquired and 64% of nosocomial peritonitis. The presence of one or more co-morbidities [odds ratio (OR) = 3.17; P = 0.007], one or more severity criteria (OR = 4.90; P < 0.001) and generalized peritonitis (OR = 3.17; P = 0.006) were predictive of death. CONCLUSIONS The principal results of EBIIA are a higher diversity of microorganisms isolated in nosocomial infections and decreased susceptibility among these strains. Despite this, the adequacy of treatment is comparable in the two groups.
TL;DR: These evidence-based guidelines are an updated version of those published in 2006, produced after a literature review of the treatment and prophylaxis of methicillin-resistant Staphylococcus aureus (MRSA).
Abstract: These evidence-based guidelines are an updated version of those published in 2006. They have been produced after a literature review of the treatment and prophylaxis of methicillin-resistant Staphylococcus aureus (MRSA). The guidelines aim to complement those recently published for the antibiotic treatment of common and emerging community-onset MRSA infections in the UK. The guidelines have reviewed and updated, where appropriate, previous recommendations, taking into account any changes in the UK epidemiology of MRSA, ongoing national surveillance data and the value of new antistaphylococcal agents licensed for use in UK practice. Emerging therapies that have not been licensed for UK use are not reviewed, but their future potential role has been mentioned where deemed appropriate. Recommendations are given for the treatment of common infections caused by MRSA, elimination of MRSA from carriage sites and prophylaxis of surgical site infection.
TL;DR: MRSA ST398 isolates varied slightly in their virulence properties and spa types but differed distinctly in their antimicrobial resistance pheno- and genotypes as well as their ApaI-PFGE patterns.
Abstract: Fifty-four methicillin-resistant Staphylococcus aureus (MRSA) ST398 isolates from unrelated diseased swine collected all over Germany were comparatively investigated for their antimicrobial resistance and virulence properties, and for their genomic relatedness. MICs of 30 antimicrobial agents were determined by broth microdilution. Resistance and virulence genes were detected via a diagnostic DNA microarray and specific PCRs. The genomic relationships were determined by ApaI-PFGE, spa typing and SCCmec typing. Twenty-two distinct resistance patterns were observed. All 54 isolates were tetracycline resistant, mediated by tet(M), tet(K) and/or tet(L), with 14 isolates being only resistant to beta-lactam antibiotics and tetracyclines. Trimethoprim resistance, seen in 28 isolates, was mostly due to the gene dfrK or dfrG. Among the 24 macrolide/lincosamide-resistant isolates, the genes erm(A), erm(B) and/or erm(C) were detected. The two chloramphenicol/florfenicol-resistant isolates harboured the gene fexA. The eight gentamicin-resistant isolates carried the gene aacA/aphD. Fifty-three isolates harboured SCCmec type V elements while the remaining one carried mecA and ugpQ, but no recombinase genes. All isolates were PVL negative, but one and three isolates, respectively, were positive for the enterotoxin B and enterotoxin K and Q genes. Eight different spa types were identified with t011 being the most predominant. Six ApaI-PFGE clusters with up to nine individual patterns were detected. MRSA ST398 isolates varied slightly in their virulence properties and spa types but differed distinctly in their antimicrobial resistance pheno- and genotypes as well as their ApaI-PFGE patterns. These data underline the ability of ST398 to acquire genetic material that might increase antimicrobial resistance and virulence
TL;DR: The aim of this work was to investigate the replicons involved in the emergence and spread of ESBLs in relation to ESBL type and found resistance genes borne by the narrow host-range IncF replicon spread readily as this replicon is well adapted to E. coli.
Abstract: Objectives Escherichia coli producing CTX-M-15 and CTX-M-14 extended-spectrum beta-lactamases (ESBLs) are spreading worldwide. The aim of this work was to investigate the replicons involved in the emergence and spread of ESBLs in relation to ESBL type. Methods A collection of 125 TEM, SHV and CTX-M ESBL-producing E. coli strains was analysed. The replicons carrying the ESBLs and the total plasmid content of the strains have been characterized by PCR replicon typing in relation to the type of ESBL. The ESBL replicons were then compared with the replicon content of E. coli strains carrying TEM-1 or inhibitor-resistant TEM (IRT) beta-lactamases. Results IncF plasmids were the most frequently carried replicons in our collection, but none carried TEM ESBL. Of TEM ESBLs, 67% were carried on IncA/C replicons except for TEM-52 genes, which were carried preferentially on IncI1 replicons. Although CTX-M enzymes can be carried by various replicons, the great majority of genes encoding CTX-M-14 and CTX-M-15 ESBLs were carried by IncF replicons, as were TEM-1 and IRT beta-lactamases. Conclusions Resistance genes borne by the narrow host-range IncF replicon spread readily as this replicon is well adapted to E. coli. This is observed for blaTEM-1 and blaCTX-M-15 and, to a lesser extent, for blaCTX-M-14. Transposition immunity seems to play an important role in the diffusion process.
TL;DR: The co-administration of DNase and AlgL is essential for enhanced activity in reducing biofilm growth and sputum bacterial counts, and while mucin retards bactericidal activity, NAC does not improve aminoglycosidic activity.
Abstract: Objectives: This study evaluated the potential of DNase, alginate lyase (AlgL) and N-acetylcysteine (NAC) in enhancing the in vitro bactericidal activity of conventional (free) and vesicle-entrapped (liposomal) gentamicin, amikacin and tobramycin. Methods: The MICs and biofilm eradication for two clinical isolates of Pseudomonas aeruginosa (a mucoid strain and a non-mucoid strain) were determined in the presence and absence of AlgL. The co-activity of aminoglycosides with DNase and/or AlgL against endogenous P. aeruginosa in cystic fibrosis (CF) sputum was also measured. The inhibitory effects of mucin in the presence and absence of the mucolytic agent NAC on aminoglycosidic activity were also examined. Results: The MIC values of the liposomal aminoglycosides were similar to or lower than those of free aminoglycosides. Biofilm formation increased the bactericidal concentrations of these drugs by 8- to 256-fold and treatment with AlgL improved killing of the mucoid strain. The activity of some aminoglycosides against the sputum was increased by the addition of DNase or AlgL (P 0.05). Tobramycin was the most effective aminoglycoside to reduce biofilms and sputum. Conclusions: Liposomal aminoglycosides do not fare better than conventional forms. The coadministration of DNase and AlgL is essential for enhanced activity in reducing biofilm growth and sputum bacterial counts. While mucin retards bactericidal activity, NAC does not improve aminoglycosidic activity.
TL;DR: The detection of KPC-Kp in an LTACH represents a serious infection control and therapeutic challenge in a new clinical setting and the speed at which the epidemic is spreading in the healthcare system mandates urgent action.
Abstract: Results: Seven KPC-Kp strains were isolated from different patients located at a single LTACH, with a further three isolates being recovered from patients at different hospitals. All KPC-Kp isolates in patients from the LTACH and from one hospital patient were genetically related and shared PFGE patterns that clustered with known sequence type (ST) 258 strains. These strains were highly resistant to carbapenems (MICs� 32 mg/L) due to an increased level of KPC expression and loss of Omps. Rectal colonization was documented in all LTACH patients with KPC-Kp isolates. Treatment failures were common (crude mortality rate of 69%). Active surveillance and enhanced infection control practices terminated the KPC-Kp outbreak. Conclusions: The detection of KPC-Kp in an LTACH represents a serious infection control and therapeutic challenge in a new clinical setting. The speed at which the epidemic of KPC-Kp is spreading in our healthcare system mandates urgent action.
TL;DR: Nisin is more effective against S. aureus whereas lacticin 3147 possesses greater potency against VRE, and the modifications responsible for the vancomycin-resistant phenotypes of hVISA and VISA strains also provide protection against the two lantibiotics.
Abstract: Objectives Our goal was to compare the activities of lacticin 3147 and nisin, two of the most well characterized lantibiotics, against antibiotic-resistant staphylococci and enterococci. Methods We determined the MICs of lacticin 3147 and nisin for 20 strains of methicillin-resistant Staphylococcus aureus (MRSA), 20 strains of vancomycin-resistant enterococci (VRE), 6 strains of S. aureus with intermediate resistance to vancomycin (VISA), 5 strains of heterogeneous vancomycin-intermediate S. aureus (hVISA) and 4 strains of S. aureus that are susceptible to methicillin. Results Lacticin 3147 displayed potent activity against VRE with MIC values between 1.9 and 7.7 mg/L, and varying levels of activity against S. aureus strains (MRSA, 1.9-15.4 mg/L; laboratory strains, >or=15.4 mg/L; hVISA, 15.4-30.9 mg/L; VISA, >or=61.8 mg/L). Nisin was more active against the S. aureus strains in general (MRSA and laboratory strains, 0.5-4.1 mg/L; VISA and hVISA, 2 to >or=8.3 mg/L), but was less effective than lacticin 3147 against VRE (2 to >or=8.3 mg/L). Conclusions Nisin is more effective against S. aureus whereas lacticin 3147 possesses greater potency against VRE. The modifications responsible for the vancomycin-resistant phenotypes of hVISA and VISA strains also provide protection against the two lantibiotics.
TL;DR: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35% and underlying disease-related factors had a major impact on results.
Abstract: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < 50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < 35%. Underlying disease-related factors had a major impact on results.