Showing papers in "Journal of Antimicrobial Chemotherapy in 2008"
TL;DR: These catheters are non-toxic and are capable of targeted and sustained release of silver at the implantation site and may be useful in reducing the risk of infectious complications in patients with indwellingCatheters.
Abstract: Objectives: To test the antimicrobial activity and evaluate the risk of systemic toxicity of novel catheters coated with silver nanoparticles. Methods: Catheters were coated with silver using AgNO3, a surfactant and N,N,N 0 ,N 0 -tetramethylethylenediamine as a reducing agent. Particle size was determined by electron microscopy. Silver release from the catheters was determined in vitro and in vivo using radioactive silver ( 110m Ag 1 ). Activity on microbial growth and biofilm formation was evaluated against pathogens most commonly involved in catheter-related infections, and the risk for systemic toxicity was estimated by measuring silver biodistribution in mice implanted subcutaneously with 110m Ag 1 -coated catheters. Results: The coating method yielded a thin (100 nm) layer of nanoparticles of silver on the surface of the catheters. Variations in AgNO3 concentration translated into proportional changes in silver coating (from 0.1 to 30 mg/cm 2 ). Sustained release of silver was demonstrated over a period of 10 days. Coated catheters showed significant in vitro antimicrobial activity and prevented biofilm formation using Escherichia coli, Enterococcus, Staphylococcus aureus, coagulase-negative staphylococci, Pseudomonas aeruginosa and Candida albicans. Approximately 15% of the coated silver eluted from the catheters in 10 days in vivo, with predominant excretion in faeces (8%), accumulation at the implantation site (3%) and no organ accumulation (� 0.1%). Conclusions: A method to coat plastic catheters with bioactive silver nanoparticles was developed. These catheters are non-toxic and are capable of targeted and sustained release of silver at the implantation site. Because of their demonstrated antimicrobial properties, they may be useful in reducing the risk of infectious complications in patients with indwelling catheters.
593 citations
TL;DR: A theoretical description of the agar diffusion assay is sought that takes into consideration loss of antibiotic during diffusion and provides higher accuracy of the MIC determined from the assay.
Abstract: Objectives: The agar diffusion assay is one method for quantifying the ability of antibiotics to inhibit bacterial growth. Interpretation of results from this assay relies on model-dependent analysis, which is based on the assumption that antibiotics diffuse freely in the solid nutrient medium. In many cases, this assumption may be incorrect, which leads to significant deviations of the predicted behaviour from the experiment and to inaccurate assessment of bacterial susceptibility to antibiotics. We sought a theoretical description of the agar diffusion assay that takes into consideration loss of antibiotic during diffusion and provides higher accuracy of the MIC determined from the assay. Methods: We propose a new theoretical framework for analysis of agar diffusion assays. MIC was determined by this technique for a number of antibiotics and analysis was carried out using both the existing free diffusion and the new dissipative diffusion models. Results: A theory for analysis of antibiotic diffusion in solid media is described, in which we consider possible interactions of the test antibiotic with the solid medium or partial antibiotic inactivation during diffusion. This is particularly relevant to the analysis of diffusion of hydrophobic or amphipathic compounds. The model is based on a generalized diffusion equation, which includes the existing theory as a special case and contains an additional, dissipative term. Conclusions: Analysis of agar diffusion experiments using the new model allows significantly more accurate interpretation of experimental results and determination of MICs. The model has more general validity and is applicable to analysis of other dissipative processes, for example to antigen diffusion and to calculations of substrate load in affinity purification.
457 citations
TL;DR: The biocompatibility index (BI) presented may be a useful tool to evaluate antiseptic agents for use in clinical practice.
Abstract: Results: The resulting rank ordering of BI for the ratio of fibroblast cytotoxicity to E. coli toxicity was OCT > PHMB > CHX > PVP-I(o) > PVP-I(s) > BAC > CPC > TRI > MSP and that to S. aureus was OCT > PHMB > CHX > CPC > PVP-I(o) > BAC > PVP(s) > TRI > MSP. OCT and PHMB were the most suitable agents with a BI greater than 1. Conclusions: The BI presented may be a useful tool to evaluate antiseptic agents for use in clinical practice.
386 citations
TL;DR: Reliance on antibiotic history and age (> or =65 years) will contribute to missed diagnoses of community-associated CDI.
Abstract: Objectives: The aim of this study was to determine the incidence of and risk factors for communityassociated Clostridium difficile infection (CDI). Methods: Prospective surveillance of community-derived faecal samples for C. difficile cytotoxin, followed by a questionnaire-based case–control study in two distinct patient cohorts (one semi-rural and the other urban). Results: The proportion of randomly selected faecal samples positive for C. difficile cytotoxin was 2.1% in both patient cohorts (median ages 73 and 45 years for the urban and semi-rural cohorts, respectively). Exposure to antibiotics in the previous 4 weeks, particularly multiple agents (P < 0.001), aminopenicillins (P < 0.05) and oral cephalosporins (P < 0.05), was significantly more frequent among cases than controls. Hospitalization in the preceding 6 months was significantly associated with CDI (45% versus 23%; P 5 0.022). However, almost half the cases had not received antibiotic therapy in the month before C. difficile detection, and approximately one-third neither had exposure to antibiotics nor recent hospitalization. Contact with infants aged � 2 years was significantly associated with CDI (14% versus 2%; P 5 0.02). Prior exposure to gastrointestinal-acting drugs (proton pump inhibitor, H2 antagonist or non-steroidal anti-inflammatory) was not significantly more common in CDI cases. C. difficile PCR ribotype 001 caused 60% and 13% of urban and semi-rural community-associated CDI cases, respectively. Conclusions: Reliance on antibiotic history and age (� 65 years) will contribute to missed diagnoses of community-associated CDI. Potential risk factors for community-associated CDI should be explored further to explain the large proportion of cases not linked to recent antibiotic therapy or hospitalization.
383 citations
TL;DR: There is an urgent need to increase the effectiveness of interventions made by society to reduce resistance or some bacterial infections will become difficult if not impossible to treat reliably.
Abstract: Since the first usage of antimicrobials, the burden of resistance among bacteria has progressively increased and has accelerated within the last 10 years. Antibiotic resistance genes were present at very low levels prior to the introduction of antibiotics and it is largely the selective pressure of antibiotic use and the resulting exposure of bacteria, not only in humans but also in companion and food animals and the environment, which has caused the rise. The increasing mobility across the globe of people, food and animals is another factor. Examples of this are the international pandemic of different genotypes of CTX-M extended-spectrum beta-lactamases (particularly CTX-M-14 and -15) and the emergence of the carbapenemase KPC-1 in both the USA and Israel. This review details examples of both the emergence and dissemination through different genetic routes, both direct and indirect selective pressure, of significance resistance in Staphylococcus aureus, Enterococcus species, Enterobacteriaceae and Pseudomonas/Acinetobacter. The response made by society to reduce resistance involves surveillance, reduced usage, improved infection control and the introduction of new antimicrobial agents. Although efforts are being made in all these areas, there is an urgent need to increase the effectiveness of these interventions or some bacterial infections will become difficult if not impossible to treat reliably.
340 citations
TL;DR: These evidence-based guidelines have been produced after a systematic literature review of a range of issues involving prevention, diagnosis and treatment of hospital-acquired pneumonia.
Abstract: These evidence-based guidelines have been produced after a systematic literature review of a range of issues involving prevention, diagnosis and treatment of hospital-acquired pneumonia (HAP). Prevention is structured into sections addressing general issues, equipment, patient procedures and the environment, whereas in treatment, the structure addresses the use of antimicrobials in prevention and treatment, adjunctive therapies and the application of clinical protocols. The sections dealing with diagnosis are presented against the clinical, radiological and microbiological diagnosis of HAP. Recommendations are also made upon the role of invasive sampling and quantitative microbiology of respiratory secretions in directing antibiotic therapy in HAP/ventilator-associated pneumonia.
309 citations
TL;DR: In this article, the authors investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery.
Abstract: Objectives Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients are intractable antibiotic targets because of their biofilm mode of growth. We have investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery. Methods Penetration of fluorescently labelled liposomes into sputum or P. aeruginosa (PA3064) biofilms was monitored by a filter assay and by epifluorescence or confocal scanning laser microscopy. Amikacin release in vitro and rat lung levels after inhalation of nebulized material were measured by fluorescence polarization immunoassay. A 14 day agar bead model of chronic Pseudomonas lung infection in rats was used to assess the efficacy of liposomal amikacin versus free aminoglycosides in the reduction of bacterial count. Results Fluorescent liposomes penetrated readily into biofilms and infected mucus, whereas larger (1 microm) fluorescent beads did not. Amikacin release from liposomes was mediated by sputum or Pseudomonas biofilm supernatants. Rhamnolipids were implicated as the major releasing factors in these supernatants, active at one rhamnolipid per several hundred lipids within the liposomes. Inhaled liposomal amikacin was released in a slow, sustained manner in normal rat lungs and was orders of magnitude more efficacious than inhaled free amikacin in infected lungs. Conclusions Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.
302 citations
TL;DR: The CTX-M-15-producing E. coli diffusing clone is associated with a high level of antibiotic resistance and with high virulence, showing that, under certain selective pressures, the previously observed trade-off between resistance and virulence may not apply.
Abstract: Objectives A clone of CTX-M-15-producing Escherichia coli has recently been reported to be spreading through Europe and Africa. The aim of this work was to thoroughly characterize this clone. Materials and methods Representative isolates of this clone were subjected to multilocus sequence typing, O typing, virulence gene detection, adhesion assay on human cells, biofilm production assay and mouse lethality assay. Results The clone: (i) belongs to a unique B2 phylogenetic subgroup encompassing the pyelonephritogenic diffusely adhering EC7372 strain; (ii) exhibits a specific O25b molecular subtype; (iii) is identical to the E. coli clone O25:H4-ST131 producing CTX-M-15; (iv) produces biofilm; and (v) is highly virulent in mice despite lacking classical extraintestinal pathogenicity islands (except for high pathogenicity island) and the afa/dra gene. Conclusions The CTX-M-15-producing E. coli diffusing clone is associated with a high level of antibiotic resistance and with high virulence, showing that, under certain selective pressures, the previously observed trade-off between resistance and virulence may not apply.
297 citations
TL;DR: The emergence of reduced susceptibility to metronidazole is demonstrated in 24.4% of the recent C. difficile ribotype 001 isolates from the authors' institution, which could have implications in the clinical setting due to the poor penetration of metronIDazole into the colon.
Abstract: OBJECTIVES: Antimicrobial treatment for Clostridium difficile infection (CDI) has typically been metronidazole, although reports have questioned the efficacy of this option. We screened recently isolated C. difficile (2005-06) for susceptibility to metronidazole and compared results for historic isolates (1995-2001). METHODS: C. difficile ribotypes 001 (n = 86), 106 (n = 81) and 027 (n = 48) and isolates from the 10 other most prevalent ribotypes in Leeds (n = 57) were screened using spiral gradient endpoint analysis (SGE). C. difficile with metronidazole SGE MICs > or = 6 mg/L were analysed further by agar incorporation and Etest. Multiple-locus variable-number tandem-repeat analysis (MLVA) typing was performed for 28 C. difficile isolates. RESULTS: No reduced metronidazole susceptibility was observed in C. difficile ribotypes 106 and 027 (geometric mean SGE MICs 1.11 and 0.90 mg/L, respectively). In contrast, 21 (24.4%) C. difficile ribotype 001 demonstrated reduced susceptibility to metronidazole (geometric mean SGE MICs 3.51 mg/L, P < 0.001). Variations in susceptibility were observed relating to the method and media, but increased metronidazole MICs were confirmed by an agar incorporation method. Geometric mean agar incorporation MICs for historic C. difficile ribotype 001 (n = 72) were 1.03 (range 0.25-2) mg/L compared with 5.94 (4-8) mg/L (P < 0.001) for recent isolates displaying reduced metronidazole susceptibility. MLVA typing revealed two clonal complexes of C. difficile with reduced susceptibility to metronidazole. CONCLUSIONS: We have demonstrated the emergence of reduced susceptibility to metronidazole in 24.4% of the recent C. difficile ribotype 001 isolates from our institution. Our observations could have implications in the clinical setting due to the poor penetration of metronidazole into the colon.
260 citations
TL;DR: Curcumin dramatically inhibited the adhesion of Candida species isolated from AIDS patients to BEC, demonstrating that curcumin is a promising lead compound that warrants further investigation into its therapeutical use in immunocompromised patients.
Abstract: Received 19 August 2008; returned 21 October 2008; revised 28 October 2008; accepted 5 November 2008Objectives: The antifungal activity of curcumin was evaluated against 23 fungi strains and its in vitroinhibitory effect on the adhesion of Candida species to human buccal epithelial cells (BEC) was alsoinvestigated.Methods: The antifungal susceptibility was evaluated by broth microdilution assay following the CLSI(formerly the NCCLS) guidelines. The inhibitory effect of curcumin on the cell adhesion was performedwith Candida species and BEC.Results: Paracoccidioides brasiliensis isolates were the most susceptible to curcumin while thegrowth of Aspergillus isolates was not affected. Curcumin was much more efficient than fluconazole ininhibiting the adhesion of Candida species to BEC, particularly those strains isolated from the buccalmucosa of AIDS patients.Conclusions: The lack of antifungal compounds with reduced side effects highlights the importance ofstudying natural products for this purpose. Curcumin was a more potent antifungal than fluconazoleagainst P. brasiliensis, the causal agent of the neglected disease paracoccidioidomycosis. Curcumindramatically inhibited the adhesion of Candida species isolated from AIDS patients to BEC, demon-strating that curcumin is a promising lead compound that warrants further investigation into its thera-peutical use in immunocompromised patients.Keywords: antifungal activity, adhesion, MIC, natural products
249 citations
TL;DR: It is demonstrated that the pMLST method can contribute to the epidemiological description of circulation of specific resistance plasmids among beta-lactamase producers isolated from animals and humans.
Abstract: Received 17 January 2008; returned 11 February 2008; revised 28 February 2008; accepted 29 February 2008 Objectives: Plasmids belonging to incompatibility group I1 (IncI1) are widespread in Enterobacteriaceae and are characterized by the presence of a cluster of genes encoding the type IV pili, contributing to the virulence of Shiga-toxigenic Escherichia coli. Recently, IncI1 plasmids were identified in E. coli and Salmonella strains of animal origin as responsible for the dissemination of b-lactamase genes. Plasmid multilocus sequence typing (pMLST) was developed to discern naturally occurring IncI1 plasmids in homogeneous groups according to their allele assortment. Methods: pMLST was developed by selecting multiple target genes on the available complete IncI1 plasmid DNA sequences. Sixteen plasmids, all assigned to the IncI1 group by the PCR-based replicon typing method, were included in this study. They were analysed for b-lactamase genes and typed by restriction fragment length polymorphism (RFLP) and pMLST. Results: Sixteen plasmids identified in E. coli and Salmonella isolated from animals and humans in different countries carried blaCMY-2, blaCTX-M-15, blaCTX-M-1, blaCTX-M-14, blaTEM-52, blaSHV-12 or blaTEM-1 b-lactamase genes. These plasmids were classified by RFLP in nine different groups corresponding to the nine sequence types determined by pMLST. Conclusions: The pMLST method was suitable for rapid and easy subtyping of IncI1 plasmids. This study demonstrates that the pMLST method can contribute to the epidemiological description of circulation of specific resistance plasmids among b-lactamase producers isolated from animals and humans.
TL;DR: The results suggest that both acquisition from a common source and person-to-person transmission might contribute to ESBL dissemination.
Abstract: Results: The prevalence of faecal carriage was 67.9% in patients with UTI, 27.4% in household members, 15.6% in non-household relatives and 7.4% in unrelated patients. Being a relative of a patient with UTI was independently associated with an increased risk of being a carrier. Among the relatives, multivariate analysis showed that those eating their main meal outside their own home >15 days during the previous month were less likely to be faecal carriers (OR 5 0.2; 95% CI: 0.06–0.6; P 5 0.007). The faecal isolates of patients with UTI were CTX-M-producers in 66.6% and SHV-producers in 33.3% of the cases, while the percentages for other population groups were 40% to 55.5% and 50% to 75%, respectively. Of the 19 families with >1 carrier member, 8 families had 2 members who shared clonally related isolates, 8 families had 2 members carrying different clones producing the same enzymes and there were 3 families where all members had different enzyme-producing clones. Conclusions: Our results suggest that both acquisition from a common source and person-to-person transmission might contribute to ESBL dissemination.
TL;DR: Down-regulation of antioxidant enzymes in P. aeruginosa biofilms may enhance the rate of mutagenic events due to the accumulation of DNA damage and provide a further source of antibiotic-resistant mutants in the CF lung.
Abstract: Objectives: Isolates of Pseudomonas aeruginosa from cystic fibrosis (CF) patients are frequently hypermutable due to selection of mutants with defects in DNA repair genes such as mutS. Since P. aeruginosa grows as a biofilm within the infected CF lung, it is possible that this mode of growth enhances the mutability of the organism thereby increasing the opportunity to derive permanent hypermutators through mutation in DNA repair genes. We have now conducted experiments to examine this possibility. Methods: Using established procedures, we examined the mutability of P. aeruginosa PA01 in planktonic cultures and in biofilm cultures generated by growth in a Sorbarod system. Transcriptional profiling by DNA microarray was used to compare gene expression in planktonic and biofilm cells. Results: Mutation frequency determinations for resistance to rifampicin and ciprofloxacin demonstrated that biofilm cultures of P. aeruginosa displayed up to a 105-fold increase in mutability compared with planktonic cultures. Several genes (ahpC, katA, sodB and PA3529, a probable peroxidase) that encode enzymes conferring protection against oxidative DNA damage were down-regulated in biofilm cells. In particular, katA, which encodes the major pseudomonal antioxidant catalase, was down-regulated 7.7-fold. Conclusions: Down-regulation of antioxidant enzymes in P. aeruginosa biofilms may enhance the rate of mutagenic events due to the accumulation of DNA damage. Since P. aeruginosa forms biofilms in the CF lung, this mode of growth may enhance the direct selection of antibiotic-resistant organisms in CF patients and also increase the opportunity to derive permanent hypermutators thereby providing a further source of antibiotic-resistant mutants in the CF lung.
TL;DR: These guidelines have been developed to provide general practitioners and other community- and hospital-based healthcare professionals with pragmatic advice about when to suspect MRSA infection in the community, when and what cultures should be performed and what should be the management options, including the need for hospitalization.
Abstract: These guidelines have been developed by a Working Party convened on behalf of the British Society for Antimicrobial Chemotherapy. Their aim is to provide general practitioners and other community- and hospital-based healthcare professionals with pragmatic advice about when to suspect MRSA infection in the community, when and what cultures should be performed and what should be the management options, including the need for hospitalization.
TL;DR: Interventions aimed at preventing self-medication should include public education, enforcing regulations regarding the sale of antibiotics, and implementing laws for dispensing exact prescribed tablet quantities in pharmacies.
Abstract: Background: Self-medication with antibiotics occurs among the population in Europe, particularly in southern and eastern countries. We studied the impact of predisposing factors (e.g. attitudes and knowledge concerning antibiotic use and self-medication) and enabling factors (country wealth and healthcare system factors) on self-medication with antibiotics in Europe. Methods: In this follow-up of a previous European survey, we interviewed a subsample of 1101 respondents. A multilevel analysis with two levels (respondent and country) was performed. Variables that were statistically significantly different between users and non-users of self-medication were considered for inclusion into the multilevel regression analyses. Results: Predisposing factors included individual-level characteristics. High perceived appropriateness of self-medication with antibiotics for bronchitis and an attitude favouring antibiotic use for minor ailments were related to a higher likelihood of self-medication. Enabling factors included individual and country data. At the individual level, perceived availability of antibiotics without a prescription was related to increased probability of self-medication. At the country level, higher gross domestic product (wealth) and exact dispensation of prescribed tablet quantities by pharmacies were independently associated with lower likelihood of self-medication. Conclusions: Interventions aimed at preventing self-medication should include public education, enforcing regulations regarding the sale of antibiotics, and implementing laws for dispensing exact prescribed tablet quantities in pharmacies. With the included determinants, we explained almost all the variance at the country level, but not at the individual level. Future studies to increase our understanding of determinants of self-medication with antibiotics should focus on individual-level factors such as doctor-patient relationships and patient satisfaction.
TL;DR: To investigate the molecular epidemiology of ciprofloxacin-resistant CTX-M-15-producing Klebsiella pneumoniae epidemic clones isolated from six nosocomial outbreaks and sporadic cases during 2005 in Hungary, three genetic clusters defined as ECs are revealed.
Abstract: Objectives To investigate the molecular epidemiology of ciprofloxacin-resistant CTX-M-15-producing Klebsiella pneumoniae epidemic clones (ECs) isolated from six nosocomial outbreaks and sporadic cases during 2005 in Hungary. Methods Two hundred and eighty-one extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae clinical isolates collected from 41 centres were submitted to the National ESBL Reference Laboratory for further investigations. Of the 281 strains, 75 isolates proved to be SHV producers, whereas 6 isolates were ciprofloxacin-susceptible CTX-M-type ESBL producers. One hundred and ninety-six ciprofloxacin-resistant CTX-M-type beta-lactamase-producing isolates collected from 35 centres were subjected to macrorestriction profile analysis. Furthermore, molecular typing was performed by PCR and sequencing of several antibiotic resistance genes, plasmid profile analysis, transfer of resistance determinants and multilocus sequence typing (MLST). Results PFGE revealed the existence of three genetic clusters defined as ECs, where 129 isolates belonged to the previously described Hungarian EC (HEC), 46 isolates to epidemic clone II (EC II) and 21 isolates to epidemic clone III (EC III), respectively. All isolates harboured plasmids ranging from 2.0 to 230 kb. PstI digestion of plasmid DNA from transconjugants/transformants revealed diverse restriction patterns from distinct ECs. Sequence analysis of beta-lactamase genes from 19 selected isolates detected bla(CTX-M-15) and bla(OXA-1) in strains from all three ECs and bla(TEM-1) in EC III isolates located on large plasmids. ISEcpI associated with CTX-M-15 was detected only on a 50 kb non-conjugative plasmid from EC III. MLST identified three allelic profiles: ST 15 (HEC), ST 11 (EC III) and the novel ST 147 (EC II), which correspond to the PFGE clusters, respectively. Conclusions In 2005, 97% of all CTX-M-producing K. pneumoniae isolates detected across Hungary were highly ciprofloxacin-resistant CTX-M-15 producers and represented just three stable genetic clones.
TL;DR: The rest of the antifungals tested showed very poor activity against Fusarium, confirming the multiresistant nature of this genus.
Abstract: Objectives To analyse the susceptibility pattern of a collection of Fusarium clinical isolates. Methods The antifungal susceptibility pattern of 67 isolates of Fusarium was analysed. Strains were identified by morphological and molecular methods by means of sequencing elongation factor alpha. Results and conclusions Six different species were identified. Fusarium solani was the most frequently isolated, followed by Fusarium oxysporum, Fusarium proliferatum and Fusarium verticilloides. Amphotericin B was the only drug with in vitro activity (range: 0.015-32 mg/L). The rest of the antifungals tested (itraconazole, voriconazole, ravuconazole, posaconazole and terbinafine) showed very poor activity against Fusarium, confirming the multiresistant nature of this genus.
TL;DR: Conjugation and Southern hybridization revealed that qnrA, aac(6')-Ib-cr and ESBL-encoding genes were always located on the same plasmids.
Abstract: Results: Twenty-nine (8.0%) of 362 isolates were positive for qnr genes, and the qnrA-, qnrB- and qnrS-type genes were detected alone or in combination in 13 (3.6%), 8 (2.2%) and 9 (2.5%), respectively. Sixty-two (17.1%) isolates were positive for aac(6 0 )-Ib, of which 36 (9.9% of all) had the -cr variant. Conjugation and Southern hybridization revealed that qnrA, aac(6 0 )-Ib-cr and ESBL-encoding genes were always located on the same plasmids. Conclusions: qnr and aac(6 0 )-Ib-cr genes were detected in 8.0% and 9.9% of ESBL-producing E. coli and K. pneumoniae, respectively. The plasmids carrying the qnr gene could be transferred by conjugation together with ESBL-encoding genes and aac(6 0 )-Ib-cr.
TL;DR: Tigecycline showed considerable, though not consistent, antimicrobial activity against MDR (including carbapenem-resistant) Acinetobacter spp.
Abstract: Objectives: New antibacterial agents are required for the treatment of infections caused by multidrugresistant (MDR) Acinetobacter spp. Whether tigecycline constitutes an effective treatment option or not, is not well established. We sought to evaluate the available evidence regarding the microbiological activity and clinical effectiveness of tigecycline for MDR (including the subset of carbapenemresistant) Acinetobacter spp. Methods: We searched PubMed for relevant articles and extracted/evaluated the available evidence. Results: We identified 22 microbiological studies reporting data for 2384 Acinetobacter spp. (1906 Acinetobacter baumannii). Susceptibility of at least 90% of the Acinetobacter isolates to tigecycline (with an MIC breakpoint of susceptibility � 2 mg/L) was noted in 9/18 studies reporting data on MDR Acinetobacter and in 7/15 studies reporting specific data on carbapenem-resistant Acinetobacter .I n an additional study reporting data for both resistance categories, adequate susceptibility of Acinetobacter spp. was observed by one (broth microdilution) of the methods employed. The effectiveness of tigecycline for MDR Acinetobacter infections was evaluated in eight identified clinical studies, reporting retrospective data regarding 42 severely ill patients, among whom 31 had respiratory tract infection (in 4 cases with secondary bacteraemia) and 4 had bacteraemia. Tigecycline therapy (in combination with other antibiotics in 28 patients) was effective in 32/42 cases. In three cases, resistance to tigecycline developed during treatment. Conclusions: Tigecycline showed considerable, though not consistent, antimicrobial activity against MDR (including carbapenem-resistant) Acinetobacter spp. However, data to support its clinical use, particularly for ventilator-associated pneumonia or bacteraemia, caused by these pathogens, are still limited.
TL;DR: This review examines the epidemiology of MRSA in animals and human attendants/owners, the diagnosis and management ofMRSA colonization, infection and infection control strategies in animals.
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is increasing worldwide. Occasionally, animals are colonized or infected incidentally with human strains. Recently, however, new strains of MRSA emerging from within the animal kingdom, particularly in pigs, are causing human infection. MRSA has been reported in species as diverse as companion animals, horses and pigs, through to chinchillas, bats and parrots. In contrast, whereas strains of community-associated MRSA, the majority of which carry genes encoding Panton-Valentine leucocidin, are spreading rapidly in human populations, only sporadic cases have been reported in animals to date. Although MRSA has been found in some meat products, the implications for human infection through consumption are unclear. This review examines the epidemiology of MRSA in animals and human attendants/owners, the diagnosis and management of MRSA colonization, infection and infection control strategies in animals.
TL;DR: Tigecycline is microbiologically active against almost all of the ESBL or MDR E. coli isolates and the great majority of ESBL and MDR Klebsiella spp.
Abstract: Objectives: Antimicrobial drug resistance is spreading among Enterobacteriaceae, limiting the utility of traditionally used agents. We sought to systematically review the microbiological activity and clinical effectiveness of tigecycline for multidrug-resistant (MDR) Enterobacteriaceae, including those resistant to broad-spectrum b-lactams due to the expression of extended-spectrum b-lactamases (ESBLs), AmpC enzymes and carbapenemases (including metallo-b-lactamases). Methods: PubMed was searched for articles including relevant data. Results: Twenty-six microbiological and 10 clinical studies were identified. Tigecycline was active against more than 99% of 1936 Escherichia coli isolates characterized by any of the above resistance patterns (including 1636 ESBL-producing isolates) using the US Food and Drug Administration (FDA) breakpoint of susceptibility (MIC � 2 mg/L). Findings were not different using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint (� 1 mg/L). Susceptibility rates for Klebsiella spp. with any of the above resistance patterns were 91.2% for 2627 isolates by the FDA criteria and 72.3% for 1504 isolates by the EUCAST criteria (92.3% for 2030 and 72.3% for 1284 ESBLproducing isolates, by the FDA and EUCAST criteria, respectively). The degree of microbiological activity of tigecycline against 576 MDR Enterobacter spp. isolates was moderate. In clinical studies, 69.7% of the 33 reported patients treated with tigecycline achieved resolution of an infection caused by a carbapenem-resistant or ESBL-producing or MDR Enterobacteriaceae. Conclusions: Tigecycline is microbiologically active against almost all of the ESBL or MDR E. coli isolates and the great majority of ESBL or MDR Klebsiella spp. isolates. Further evaluation of its clinical utility against such resistant Enterobacteriaceae, particularly regarding non-labelled indications, is warranted.
TL;DR: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations.
Abstract: Results: The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T> C( P T( P T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs). Conclusions: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of nonnucleoside reverse transcriptase inhibitors to Black patients.
TL;DR: High proportion of clonal groups identified in different regions of Japan suggests their recent spread by mechanisms other than healthcare-associated transmission, and implies that restricting antimicrobial use in human clinical settings may have limited impact on the spread of ESBL-producing E. coli.
Abstract: Introduction: In the early 2000s, there was a rapid increase in extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in hospital settings throughout Japan. The reasons for this rapid increase are unclear. Methods: Between 2002 and 2003, 142 clinical isolates of E. coli suspected of producing ESBL were obtained from 37 hospitals and commercial clinical laboratories in geographically distinct regions throughout Japan. They were tested for ESBL types and further subtyped for serogroups, fimH single nucleotide polymorphism, pulsed-field gel electrophoresis patterns and multilocus sequence type (MLST). Representative isolates were also subjected to plasmid analysis. Results: Of 142 E. coli isolates suspected of producing ESBL, 130 were confirmed as harbouring bla CTC-M by PCR analysis and sequencing. Of these, 84 (65%) harboured CTX-M-9-group bla CTX-M . Two serogroups 025 and 086 accounted for 41% of the 130 blac TCX-M -Positive E. coli. All 086 serogroup strains belonged to ST38 by MLST and they formed 18% of all the bla CTX-M -Positive E. coli. Serogroup 025 strains belonged to ST131 and ST73, and formed 21% and 1% of bla CTX-M -Positive E. coli, respectively. Seven characterized plasmids carrying bla CTX-M genes belonged to three distinct incompatibility groups: IncF, IncN and Incl1. Conclusions: In this study, clonally related strains of E. coli accounted for a large proportion of bla CTX-M -Positive E. coli. This high proportion of clonal groups identified in different regions of Japan suggests their recent spread by mechanisms other than healthcare-associated transmission. These observations imply that restricting antimicrobial use in human clinical settings may have limited impact on the spread of ESBL-producing E. coli.
TL;DR: The data suggest that monotherapy with Colistin methanesulfonate, the parenteral form of colistin, and long dosage intervals may be problematic for the treatment of infections caused by multidrug-resistant K. pneumoniae, particularly for colistIn-heteroresistant strains.
Abstract: Methods: Twenty-one multidrug-resistant clinical K. pneumoniae isolates from 16 different clinical sites worldwide were employed. The genetic relatedness of these isolates was examined with PFGE. In vitro pharmacodynamic properties of colistin (sulphate) were investigated by studying the MICs, mutation prevention concentrations, time–kill kinetics, population analysis profiles and the postantibiotic effect (PAE). Time–kill was studied with three clinical isolates plus ATCC 13883 at concentrations ranging from 0.5 to 643 MIC. The PAE was examined after 20 min of exposure of these isolates. Results: The 22 isolates belonged to 18 different PFGE groups. For susceptible isolates, colistin MICs ranged from 0.125 to 1 mg/L. Six isolates were colistin-resistant with MICs of � 32 mg/L. Colistin heteroresistance was observed in 15 of 16 isolates considered colistin-susceptible based on MICs. For susceptible isolates, colistin showed extremely rapid killing; however, regrowth was observed as early as 2 h after treatment and substantial regrowth at 24 h even at concentrations up to 643 MIC for some isolates. Colistin exhibited no or very modest PAE against the isolates tested. Conclusions: The data suggest that monotherapy with colistin methanesulfonate, the parenteral form of colistin, and long dosage intervals may be problematic for the treatment of infections caused by multidrug-resistant K. pneumoniae, particularly for colistin-heteroresistant strains. Further investigation on combination therapy of colistin with other antibiotics is warranted.
TL;DR: The future spread of the ST131 clone, and its UK variants, should be monitored closely and the pathogenic mechanisms explaining their success should be investigated.
Abstract: Objectives: Uropathogenic and invasive Escherichia coli O25:H4-ST131 isolates producing CTX-M-15 extended-spectrum b-lactamase (ESBL) enzymes have recently been shown to be disseminated across the globe. In the UK, many CTX-M-15 ESBL-producing E. coli strains have been previously defined as belonging to the epidemic strains A‐E, as determined by PFGE. The present study was carried out to define the relationship between these two groups of pathogenic E. coli. Methods: Multilocus sequence typing and PFGE were used for molecular characterization of a collection of 61 ESBL-producing E. coli isolates from across the UK. Results: Strains A to E all belonged to the ST131 clone, further underscoring the epidemiological importance of this lineage. Conclusions: The future spread of the ST131 clone, and its UK variants, should be monitored closely and the pathogenic mechanisms explaining their success should be investigated.
TL;DR: Overall these new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance, and are probably similar to voriconazole and caspofungin (aminocandin).
Abstract: Although several new antifungal drugs have been licensed in the last 5 years, some patients remain difficult to treat. The main reasons for this include intrinsic or acquired antifungal resistance, organ dysfunction preventing the use of some agents and drug interactions. In addition, some drugs penetrate poorly into sanctuary sites including eye and urine, and others are associated with considerable adverse events. Here, we review the preclinical and clinical development progress with four new antifungal agents: isavuconazole, ravuconazole, albaconazole and aminocandin. Isavuconazole and ravuconazole are extremely similar, with a broad spectrum of activity, a very long half-life and large volume of distribution and good in vivo data supporting their efficacy in invasive aspergillosis and candidosis. Both compounds are in early Phase 3 development. Albaconazole has also shown very potent activity against species of Candida, Cryptococcus and Aspergillus. It was well tolerated and effective in women with vaginal candidosis. Aminocandin is an intravenous-only echinocandin with in vivo activity against Candida spp. and Aspergillus spp. Its extended half-life probably permits dosing less frequently than once a day. Overall these new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. Their antifungal spectrum is narrower than posaconazole and probably similar to voriconazole (isavuconazole and ravuconazole) and caspofungin (aminocandin). Licensure and determination of their place in clinical practice requires randomized clinical studies, which are or will be underway.
TL;DR: Overall, clonal dissemination was noted within medical centres; however, genetic relatedness was also noted among class D carbapenemase-producing A. baumannii isolates recovered from different countries, emphasizing the epidemic potential of these bacteria.
Abstract: Objectives The aim of this study was to evaluate the occurrence and dissemination of acquired carbapenem-hydrolysing class D beta-lactamase (class D carbapenemase)- and metallo-beta-lactamase (MBL)-encoding genes among Acinetobacter spp. isolates recovered from medical centres in the Asia-Pacific (APAC) region. Methods During 2006-07, 41 medical centres located in 10 countries in the APAC region forwarded to a central monitoring site 544 Acinetobacter spp. isolates, which were tested for susceptibility by the reference broth microdilution method. Isolates non-susceptible to imipenem or meropenem (MIC>or=8 mg/L) were screened for OXA-23-, OXA-24/40-, OXA-58- and MBL-encoding genes and confirmed by sequencing. Clonality was assessed by ribotyping and PFGE. Results Polymyxins (99.1% susceptible) and tigecycline (98.9% susceptible) were the most active antimicrobial agents tested. Among the isolates, 230 (42.3%) were non-susceptible to imipenem or meropenem, and class D carbapenemase- or MBL-encoding genes were detected in 162 (70.4%). blaOXA-23 was found in isolates recovered from six countries, while blaOXA-24/40 and blaOXA-58 were less common. Several isolates harboured more than one class D carbapenemase, and MBL-encoding genes were detected in one Acinetobacter johnsonii from the Philippines (blaIMP-4) and one Acinetobacter baumannii from Korea (blaVIM-2)). Overall, clonal dissemination was noted within medical centres; however, genetic relatedness was also noted among class D carbapenemase-producing A. baumannii isolates recovered from different countries. Conclusions This study shows a high distribution of class D carbapenemase-encoding genes, mainly blaOXA-23, in Acinetobacter spp. isolates. In addition, clonal dissemination among medical centres located in different countries in the APAC region, previously documented in many regions of Europe, emphasizes the epidemic potential of these bacteria.
TL;DR: Zygomycosis is a frequently lethal invasive infection in high-risk patients such as the immunocompromised and patients with type 2 diabetes mellitus and there are recent reports suggesting that it has increased in incidence since the introduction of voriconazole.
Abstract: Zygomycosis is a frequently lethal invasive infection in high-risk patients such as the immunocompromised [especially haematopoietic stem cell transplant (HSCT) recipients] and patients with type 2 diabetes mellitus. However, zygomycosis has also been reported in individuals without known risk factors. The causative fungi are members of the order Mucorales and individual species within this group require a high level of laboratory skill for their identification. These organisms are resistant to voriconazole and also to the echinocandins, and although zygomycosis is less commonly documented than invasive aspergillosis in leukaemic and HSCT patients, there are recent reports suggesting that it has increased in incidence since the introduction of voriconazole. Zygomycosis can present clinically as rhinocerebral, pulmonary or disseminated disease which progresses rapidly. The management of cases is based on early diagnosis, surgical debridement when possible and aggressive antifungal therapy. Based on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is a new orally administered triazole antifungal and the first member of this class to have comparable in vitro activity to amphotericin B against most zygomycetes. Studies of salvage therapy of zygomycosis with posaconazole have yielded promising results and there are additional case reports of successful outcomes using these and other antifungal drugs as combination therapy. Adjunctive approaches that are showing promise but with limited clinical experience are iron chelation and immunotherapy.
TL;DR: An aggregate-level relation between the monthly MRSA incidence and the use of different antibiotic classes and increased consumption of ABHR after a successful hand hygiene campaign is observed, while no association with ABHR use was detected for C. difficile.
Abstract: OBJECTIVES: The aim of this study was to determine the temporal relation between the use of antibiotics and alcohol-based hand rubs (ABHRs) and the incidence of methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. METHODS: An interventional time-series analysis was performed to evaluate the impact of two promotion campaigns on the consumption of ABHRs and to assess their effect on the incidence of non-duplicate clinical isolates of MRSA and C. difficile from February 2000 through September 2006. This analysis was combined with a transfer function model of aggregated data on antibiotic use. RESULTS: Consumption of ABHRs correlated with MRSA, but not with C. difficile. The final model demonstrated the immediate effect of the second hand hygiene promotion campaign and an additional temporal effect of fluoroquinolone (time lag, 1 month; i.e. antibiotic effect delayed for 1 month), macrolide (lag 1 and 4 months), broad-spectrum cephalosporins (lag 3, 4 and 5 months) and piperacillin/tazobactam (lag 3 months) use. The final model explained 57% of the MRSA variance over time. In contrast, the model for C. difficile showed only an effect for broad-spectrum cephalosporins (lag 1 month). CONCLUSIONS: We observed an aggregate-level relation between the monthly MRSA incidence and the use of different antibiotic classes and increased consumption of ABHR after a successful hand hygiene campaign, while no association with ABHR use was detected for C. difficile.
TL;DR: There may be a role for essential oils, in particular EO, for improved skin antisepsis when combined with chlorhexidine digluconate, alone and in combination with tea tree oil and thymol.
Abstract: Objectives Effective skin antisepsis and disinfection of medical devices are key factors in preventing many healthcare-acquired infections associated with skin microorganisms, particularly Staphylococcus epidermidis. The aim of this study was to investigate the antimicrobial efficacy of chlorhexidine digluconate (CHG), a widely used antiseptic in clinical practice, alone and in combination with tea tree oil (TTO), eucalyptus oil (EO) and thymol against planktonic and biofilm cultures of S. epidermidis. Methods Antimicrobial susceptibility assays against S. epidermidis in a suspension and in a biofilm mode of growth were performed with broth microdilution and ATP bioluminescence methods, respectively. Synergy of antimicrobial agents was evaluated with the chequerboard method. Results CHG exhibited antimicrobial activity against S. epidermidis in both suspension and biofilm (MIC 2–8 mg/L). Of the essential oils thymol exhibited the greatest antimicrobial efficacy (0.5–4 g/L) against S. epidermidis in suspension and biofilm followed by TTO (2–16 g/L) and EO (4–64 g/L). MICs of CHG and EO were reduced against S. epidermidis biofilm when in combination (MIC of 8 reduced to 0.25–1 mg/L and MIC of 32–64 reduced to 4 g/L for CHG and EO, respectively). Furthermore, the combination of EO with CHG demonstrated synergistic activity against S. epidermidis biofilm with a fractional inhibitory concentration index of <0.5. Conclusions The results from this study suggest that there may be a role for essential oils, in particular EO, for improved skin antisepsis when combined with CHG.