International Journal of Antimicrobial Agents

Editorial Board

2012-06-01

What's behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance

2012-04-09

Successful application of antibiotic therapy in the critically ill requires not only timely administration of an agent of appropriate spectrum but the provision of adequate drug concentrations at the site of infection . In this manner, an understanding of the interaction between pharmacokinetics, bacterial susceptibility and patient physiology is critical to improving dose selection and thus enhancing the probability of bacterial eradication and clinical cure . To date, such issues have received only minor consideration in pharmaceutical research, with doses for clinical use often based on studies in healthy volunteers and simply extrapolated into different populations. The increasing prevalence of antibiotic resistance, particularly in scenarios where dosing is suboptimal , provides further impetus to re-consider the manner in which antibiotics are employed in different clinical settings.

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

Francesco Scaglione, Liberato Berrino — 2012-01-24

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

Invasive fungal infections in patients with cancer in the Intensive Care Unit

Nikolaos V. Sipsas, Dimitrios P. Kontoyiannis — 2012-02-15

Abstract: Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients. Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs. The vast majority of IFIs in the ICU are due to Candida spp. The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU. A shift in the distribution of Candida spp. from Candida albicans to non-albicans Candida spp. has been observed both in ICUs and oncology units in the last two decades. Timely diagnosis of IC remains a challenge despite the introduction of new microbiology techniques. Delayed initiation of antifungal therapy is associated with increased mortality. Therefore, prediction rules have been developed and validated prospectively in order to identify those ICU patients at high risk for IC and likely to benefit from early treatment. These rules, however, have not been validated in cancer patients. Similarly, major clinical studies on the efficacy of newer antifungals typically do not include cancer patients. Despite the introduction of more potent and less toxic antifungals, mortality from IFIs amongst cancer patients remains high. In recent years, aspergillosis and mucormycosis have also emerged as significant causes of morbidity and mortality amongst ICU patients with haematological cancer.

Prevalence and analysis of microbiological factors associated with phenotypic heterogeneous resistance to carbapenems in Acinetobacter baumannii

2012-03-26

Abstract: The objectives of this study were to determine the prevalence of Acinetobacter baumannii with phenotypic heterogeneous resistance (PHR) to carbapenems (colonies inside the halo of inhibition) and to analyse its association with several microbiological variables. Acinetobacter baumannii isolates collected in Spain were used to analyse: (i) minimum inhibitory concentrations (MICs) of carbapenems; (ii) heteroresistance to carbapenems; (iii) genes encoding β-lactamases (bla genes); (iv) insertion sequences; and (v) inactivation of genes encoding porins (CarO, OprD and Omp33–36) and genes associated with the AdeABC efflux system (adeB, adeR and adeS). Polymerase chain reaction (PCR) amplification was used for gene detection. The rate of PHR was 20% to imipenem and 24% to meropenem. Susceptibility to imipenem was observed in 39% of PHR isolates. MICs of carbapenems for colonies were similar (±1log2 dilution) to those of their parental isolates. These colonies growing inside the inhibition halo also reproduced the PHR to carbapenems. Differences observed between PHR isolates and non-PHR isolates were: blaOXA-58-like, 57% vs. 0%; oprD-like, 96% vs. 56%; adeB, 89% vs. 94%; adeR, 82% vs. 94%; adeS, 82% vs. 94%; ISAba2, 61% vs. 31%; and ISAba3, 57% vs. 0%. No interruption of genes encoding porins or the efflux-related genes (adeB, adeR and adeS) was observed. In conclusion, A. baumannii strains with PHR to carbapenems are widespread in Spain. This phenotype is present in carbapenem-susceptible isolates as well as those that are not susceptible to carbapenems. Heteroresistance cannot explain the PHR to carbapenems, which appears to relate more to persistence or tolerance to carbapenems. blaOXA-58-like, blaOXA-51-like, ISAba2 and ISAba3 are associated with PHR to carbapenems. Inactivation of genes encoding porins or genes related to AdeABC is infrequent.

Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature

2012-04-25

Abstract: By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu50. The mutants, occurring at an extremely low rate (<1×10−11/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated ‘reverse antibiotics’.

gyrA/B fluoroquinolone resistance allele profiles amongst Mycobacterium tuberculosis isolates from mainland China

2012-04-23

Abstract: Fluoroquinolones are important second-line drugs for the treatment of tuberculosis. A comprehensive profile of resistance mutation patterns of DNA gyrase, the major target of fluoroquinolones, is crucial for molecular diagnosis of drug resistance and improvement of treatment efficacy. To investigate the mutation types of the genes encoding the A and B subunits of DNA gyrase (gyrA and gyrB, respectively) in ofloxacin- and levofloxacin-resistant Mycobacterium tuberculosis strains prevalent in mainland China, 177 clinical drug-resistant isolates collected by the National Tuberculosis Reference Laboratory of China were analysed. The GyrB single mutations (Glu498 and Gly551) and double mutation (Thr539Asn–Gly551Arg) as well as a GyrA double mutation (Asp94Asn–Gly112His) were reported to be involved in fluoroquinolone resistance for the first time. To simplify quantification of the contribution of each mutation type and mutation site to overall fluoroquinolone resistance, a mathematical method was established by assigning each resistance allele a numerical score between 5 and 50 (the larger the number, the higher the resistance level). The score of double mutants is the sum of the scores for the two single alleles. The double mutation types, including Asn538Ile(GyrB)–Asp94Ala(GyrA), Ala543Val(GyrB)–Asp94Asn(GyrA) and Ala543Val(GyrB)–Asp94Gly(GyrA) scored relatively high by this methodology.

Trending 7 years of in vitro activity of tigecycline and comparators against Gram-positive and Gram-negative pathogens from the Asia-Pacific region: Tigecycline Evaluation Surveillance Trial (TEST) 2004–2010

2012-04-25

Abstract: A total of 10948 clinical isolates was collected throughout the Asia-Pacific region as part of the Tigecycline Evaluation Surveillance Trial (TEST) during 2004–2010, consisting of 7549 Gram-negative and 3399 Gram-positive pathogens. Susceptibility trends for all species demonstrated several significant species-dependent susceptibility changes to multiple antibiotics. The most notable was minocycline, for which significant decreases in susceptibility (P<0.001) were observed for six of the ten species studied. In contrast, statistically significant susceptibility changes for tigecycline were observed in only two of the ten species, namely Klebsiella pneumoniae and Serratia marcescens. Seven years following the introduction of tigecycline into clinical use, this agent remains highly active against a wide range of pathogens from the Asia-Pacific region.

Bactericidal activity against meticillin-resistant Staphylococcus aureus of a novel eukaryotic therapeutic recombinant antimicrobial peptide

Qingtian Li, Jiewen Huang, Hongxiong Guo, Xiaokui Guo, Yongzhang Zhu, Ke Dong — 2012-04-23

Abstract: Antimicrobial peptides (AMPs) are one of several potential antibacterial agents in the current era of antibiotics facing severe challenges. In this study, the bactericidal activity and stability of two eukaryotic AMPs were determined. Both AMPs showed specific antibacterial activity in a HEK293T cell model infected with meticillin-resistant Staphylococcus aureus. The recombinant eukaryotic AMP pVAX1/hBD3-CBD showed better bactericidal activity and stability than the eukaryotic AMP pVAX1/hBD3. These results illustrate that this peptide, designed and used with eukaryotic expression and recombinant methods, should be studied and applied in further AMP research and trials.

Anti-anaerobic activity of a new β-lactamase inhibitor NXL104 in combination with β-lactams and metronidazole

L.J. Dubreuil, S. Mahieux, C. Neut, C. Miossec, J. Pace — 2012-04-23

Abstract: NXL104 is a new β-lactamase inhibitor (BLI) that inhibits class A and class C β-lactamase enzymes. In this study, the activity of NXL104 in combination with the third-generation cephalosporins ceftazidime (CAZ) and ceftriaxone (CRO) or with piperacillin (PIP) was evaluated against 316 anaerobic bacteria. Minimum inhibitory concentrations (MICs) were determined using an agar dilution method. The BLIs NXL104 or tazobactam (TAZ) were added to the β-lactams at a fixed concentration of 4mg/L. A triple combination of NXL104 with an 8:1 ratio of CAZ and metronidazole (MTZ) was also tested. The activities of CAZ, CRO and PIP in combination with NXL104 were enhanced against many of the bacteria. MIC50 values (MIC for 50% of the organisms) for CAZ+NXL104 were 8–16-fold lower than those of CAZ against Gram-negative anaerobes. Antibiotic resistance rates against all anaerobic strains were: CAZ, 37.7%; CRO, 31%; CAZ+NXL104, 15.2%; CRO+NXL104, 5.4%; and MTZ, 4.1%. No resistant strains could be observed with PIP+TAZ, PIP+NXL104 or the triple combination MTZ+CAZ+NXL104. In conclusion, the triple combination of MTZ+CAZ+NXL104 demonstrated potent antibacterial activity against anaerobes representing most clinical species. It appears appropriate for the treatment of polymicrobial infections, since CAZ+NXL104 also exhibits potent activity against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. It is currently being tested in phase 2 clinical trials for the treatment of complicated intra-abdominal infections.

Penetration of moxifloxacin into liver tissue

2012-04-23

Abstract: Moxifloxacin is considered for treatment of pyogenic liver abscesses as well as antibiotic prophylaxis in the case of hepatobiliary interventions. The aim of this study was to provide data on the pharmacokinetic (PK) profile of moxifloxacin in serum and liver tissue of patients undergoing liver resection due to primary or secondary tumours of the liver. Patients scheduled for liver resection (n=34) received moxifloxacin 400mg at randomised time intervals prior to surgery. Blood and healthy liver tissue were sampled 1.5–26h after administration of moxifloxacin. Immediately after centrifugation, plasma was separated, frozen and stored until analysis. In a subgroup of 19 patients, additional plasma specimens were obtained after 2, 4, 8, 12, 24, 36 and 48h to assess the PK profile. PK parameters of moxifloxacin were calculated applying a two-compartment model. Median (interquartile range) PK parameters were as follows: peak concentration at the end of moxifloxacin infusion (Cmax), 6.0mg/L (4.8–7.1mg/L); area under the concentration–time curve extrapolated to infinity (AUC0–∞), 51.1mgh/L (40.3–57.7mgh/L); elimination half-life, 13.2h (11.0–14.1h); volume of distribution at steady state (Vss), 138.7L (102.7–168.5L); and total body clearance (CL), 7.8L/h (6.9–9.9L/h). Mean tissue concentrations were 9.13mg/kg after 1.6–2.4h, 7.62mg/kg after 2.6–4.9h, 7.48mg/kg after 5.6–10.0h and 6.24mg/kg after 22.9–26.5h. Mean tissue:serum ratios were 2.9, 3.4, 5.0 and 12.3, respectively. The lowest tissue concentration found in the study at any time point was 2.8mg/kg. In conclusion, moxifloxacin rapidly penetrates into the liver tissue where its concentration remains high following intravenous administration. Therefore, intravenously applied moxifloxacin might be used for the treatment of bacterial liver infections such as pyogenic liver abscess as well as in pre-operative prophylaxis.

Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies

2012-04-05

Abstract: Posaconazole (PCZ) is a triazole antifungal agent that has broad activity against pathogenic fungi and is increasingly used for prophylaxis and treatment of invasive mould infections (IMIs). PCZ is only available as an oral formulation, with varying absorption from the gastrointestinal tract. However, reports correlating PCZ plasma concentrations (PPCs) with breakthrough IMIs are rare. In this study, PPCs were analysed in a prospective, observational, single-centre study and the correlation of PPCs with breakthrough IMIs in patients with haematological malignancies was evaluated. Risk factors associated with low PPCs were further evaluated. A total of 109 PPCs were measured in 34 cases receiving PCZ prophylaxis (n=31) or treatment (n=3). Levels below the target of 0.5μg/mL were detected in 24 (71%) of the 34 cases; in 15 (63%) of these 24 cases concentrations were found to be <0.20μg/mL. Three patients receiving PCZ prophylaxis met the criteria of breakthrough infection. Notably, prior to development of IMI, PPCs were below the target in all three individuals. Associated risk factors for insufficient PPCs varied from previous reports. In conclusion, these data demonstrate that therapeutic drug monitoring of PCZ is mandatory in all patients with haematological malignancies as low PPCs are common and may be associated with development of IMIs.

Role of IncHI2 plasmids harbouring blaVIM-1, blaCTX-M-9, aac(6′)-Ib and qnrA genes in the spread of multiresistant Enterobacter cloacae and Klebsiella pneumoniae strains in different units at Hospital Vall d’Hebron, Barcelona, Spain

2012-04-05

Abstract: Seven Enterobacter cloacae isolates and seven Klebsiella pneumoniae isolates harbouring a phenotype compatible with the production of a metallo-β-lactamase were recovered between 2009 and 2011 in three Intensive Care Units of Hospital Vall d’Hebron (Barcelona, Spain). The presence of blaVIM, blaIMP, blaNDM, blaCTX-M, aac(6′)-Ib, qnrA, qnrB and qnrS genes was screened by polymerase chain reaction (PCR) and sequencing. Clonal relatedness of the isolates was assessed by pulsed-field gel electrophoresis (PFGE) and, in the case of K. pneumoniae isolates, by multilocus sequence typing (MLST). PCR-based replicon typing, Southern hybridisation, plasmid double-locus sequence typing and MOB relaxase classification methods were used to identify and characterise the plasmids carrying the resistance genes. Transferability of the identified plasmids was tested by conjugation assays. All 14 isolates were found to carry blaVIM-1, blaCTX-M-9 (except one isolate), aac(6′)-Ib and qnrA genes. Clonality assessment demonstrated that E. cloacae isolates were distributed in three clonal clusters, whereas all of the K. pneumoniae isolates belonged to one unique clone, identified as sequence type ST252. All studied isolates harboured a large conjugative IncHI2 MOBH11 plasmid carrying all of the detected resistance genes. Plasmid DNA analysis showed that all of them belonged to the ST1 IncHI2 plasmid cluster and shared the same relaxase partial sequence. In conclusion, the present study describes the dissemination within a hospital of multiresistant E. cloacae and K. pneumoniae isolates producing VIM-1. A complex clonal epidemiology of the E. cloacae isolates was observed and plasmid DNA analysis strongly supports horizontal exchanges of the same IncHI2 plasmid between different strains and species.

Emergence of a novel multidrug-resistant Pseudomonas aeruginosa strain producing IMP-type metallo-β-lactamases and AAC(6′)-Iae in Japan

2012-04-09

Abstract: The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa isolates producing IMP-type metallo-β-lactamases (MBLs) and aminoglycoside 6′-N-acetyltransferase [AAC(6′)-Iae] has become a serious problem in medical settings in Japan. A total of 217 MDR P. aeruginosa isolates were obtained from August 2009 to April 2010 from patients at 144 hospitals in Japan, of which 145 (66.8%) were positive for IMP-type MBLs and AAC(6′)-Iae when tested with an immunochromatographic assay. Polymerase chain reaction (PCR) showed that these isolates were also positive for blaIMP and aac(6′)-Iae genes. When these IMP-type MBL- and AAC(6′)-Iae-producing isolates were analysed by pulsed-field gel electrophoresis (PFGE), two clusters (I and II) were detected. Most of the isolates (88.3%; 128/145) were grouped under cluster I and had multilocus sequence type ST235 and serotype O11, except for one isolate that was ST991 and serotype O3. The isolates were mainly isolated from the urinary tract (82/145; 56.6%) and respiratory tract (58/145; 40.0%). The epidemiological properties of the isolates belonging to cluster I were similar to those of MDR P. aeruginosa isolates that have been previously reported in Japan. The remaining 16 isolates belonged to cluster II, had identical PFGE patterns and were multilocus sequence type ST991 and serotype O18; all of these isolates were isolated from the respiratory tract. The properties of isolates belonging to cluster II have not been previously described, indicating that a novel IMP-type MBL- and AAC(6′)-Iae producing P. aeruginosa strain is emerging in Japan. Isolates belonging to both clusters were isolated from different parts of the country.

High clonal heterogeneity of Panton–Valentine leukocidin-positive meticillin-resistant Staphylococcus aureus strains from skin and soft-tissue infections in the Province of Bolzano, Northern Italy

2012-04-05

Abstract: Panton–Valentine leukocidin (PVL)-positive community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) isolates are widespread in many countries, with varying distribution and epidemiology. The aim of this study was to characterise 10 PVL-positive MRSA isolates collected during February 2010 to January 2011 from skin and soft-tissue infections in the North Italian Province of Bolzano. Accessory gene regulator (agr) typing, staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) gene typing, multilocus sequence typing, toxin gene profiling, polymerase chain reaction for type I arginine catabolic mobile element (ACME) and antimicrobial resistance typing were applied to the isolates. Eight different CA-MRSA clones were identified, including ST30-IVc, ST772-V, ST80-IVc, ST5-IVc, ST88-IVa, ST93-IVa, ST8-IVc and the type I ACME-positive ST8-IVa. The high heterogeneity of PVL-positive MRSA probably reflects the introduction of different clones by international travellers or immigrants.

Characterisation and clonal dissemination of OXA-23-producing Acinetobacter baumannii in Tabriz, northwest Iran

2012-04-23

Abstract: The characteristics and molecular epidemiology of carbapenemase genes amongst 68 imipenem-resistant Acinetobacter baumannii isolated from Imam Reza Hospital (Tabriz, Iran) during a 17-month period were studied. All 68 isolates were typed using sequence group-based multiplex polymerase chain reaction (PCR) to compare the clonal relationship of isolates with known international clonal lineages. Repetitive sequence-based PCR was further performed with representative isolates of each clone. PCR and sequencing were performed to detect OXA-type carbapenemases and class 1, 2 and 3 integron genes as well as to confirm the presence of insertion sequence ISAba1 upstream of blaOXA-23 and blaOXA-51-like genes. Sixty-four isolates (94%) belonged to international clone (IC) II, two isolates (3%) belonged to IC I and two isolates (3%) did not belong to known international clones. All isolates carried blaOXA-51-like, blaOXA-23 and class 1 integron genes. No other acquired blaOXA genes or class 2 or 3 integron genes were detected. Sequence analysis confirmed the presence of blaOXA-23 as well as the blaOXA-51-like variants blaOXA-66, blaOXA-69 and blaOXA-88. ISAba1 was present upstream of the blaOXA-23 gene in all of the isolates. Clonal spread of OXA-23-producing A. baumannii emphasises the need for appropriate infection control measures to prevent further spread of these multidrug-resistant organisms.

Identification and molecular characterisation of New Delhi metallo-β-lactamase-1 (NDM-1)- and NDM-6-producing Enterobacteriaceae from New Zealand hospitals

2012-04-23

Abstract: The global spread of New Delhi metallo-β-lactamase (NDM) is of significant public health concern. This study sought to determine whether blaNDM was present in Enterobacteriaceae isolates displaying resistance to carbapenems that were submitted to the National Antibiotic Reference Laboratory, Institute of Environmental Science and Research (Porirua, New Zealand) during 2009 and 2010. Isolates were tested for the presence of β-lactamase genes and 16S rRNA methylase genes by polymerase chain reaction (PCR) and sequencing. Plasmid transfer studies were undertaken on isolates found to be harbouring blaNDM. Molecular typing was performed by multilocus sequence typing (MLST). The blaNDM-1 gene was identified in four Enterobacteriaceae isolates (two Escherichia coli, one Klebsiella pneumoniae and one Proteus mirabilis) from four patients in New Zealand hospitals in 2009 and 2010. In addition, the blaNDM-6 gene, which differed from blaNDM-1 by a point mutation at position 698 (C→T), was also identified in an E. coli isolate from the same patient who harboured the blaNDM-1-positive P. mirabilis. All four patients had recently been hospitalised or received health care in India. Four of the isolates also produced a CTX-M-15 extended-spectrum β-lactamase and/or plasmid-mediated AmpC β-lactamase, and all five isolates harboured the plasmid-mediated 16S rRNA methylase rmtC gene. The E. coli types were diverse by MLST, and the K. pneumoniae isolate belonged to the internationally disseminated sequence type 11 (ST11) clone. These findings further illustrate the diversity of phenotypic and genotypic features found in association with blaNDM, in addition to documenting the international spread of this resistance mechanism, notably into a country with historically low rates of antimicrobial resistance.

Activity of ceftobiprole against Streptococcus pneumoniae isolates exhibiting high-level resistance to ceftriaxone

Todd A. Davies, Robert K. Flamm, A. Simon Lynch — 2012-04-23

Abstract: Tracking Resistance in the US Today (TRUST) 2008 surveillance data showed that 6% of Streptococcus pneumoniae were non-susceptible to ceftriaxone [minimum inhibitory concentration (MIC) ≥2μg/mL] and that 8% of the ceftriaxone-non-susceptible isolates exhibited high-level resistance (MIC≥8μg/mL). Here we describe the activity of ceftobiprole against ceftriaxone-resistant isolates and characterise the genotypic traits associated with resistance. Thirty isolates with ceftriaxone MICs≥8μg/mL were analysed by sequencing of penicillin-binding protein (PBP) and murM genes. Sequencing of pbp1a, pbp2b and pbp2x showed nine PBP patterns, with the most common (n=17) being: PBP1a T371S (STMK motif), P432T (SRNVP motif); PBP2b T446A (SSNT motif), A619G (KTGTA motif); and PBP2x T338A and M339F (STMK motif), L364F, I371T, R384G, M400T, L546V (LKSGT motif); six isolates had the same pattern without the PBP2b A619G change. For these 23 isolates, MICs were 8μg/mL for ceftriaxone, 4–8μg/mL for penicillin and 0.5–2μg/mL for ceftobiprole. The remaining seven isolates with higher MICs (ceftriaxone 8–32μg/mL, penicillin 4–32μg/mL and ceftobiprole 2–4μg/mL) had fewer PBP active-site motif substitutions. The majority of isolates (17/30) had murM alleles similar to the wild-type, whilst the rest had alleles reflecting a mosaic structure. No murM alleles were associated with higher MICs. Against these 30 isolates, ceftobiprole was 4–16-fold more active than ceftriaxone. Widely described PBP and MurM substitutions probably account for the high ceftriaxone MICs (8μg/mL) in the majority of isolates. However, seven isolates with ceftriaxone MICs of 8–32μg/mL had fewer PBP substitutions in active-site motifs, suggesting either that there is another resistance mechanism or that unique PBP mutations may contribute to high-level β-lactam resistance.

2-Hydroxyisocaproic acid (HICA): a new potential topical antibacterial agent

2012-04-09

2-Hydroxyisocaproic acid (HICA), also known as leucic acid, 2-hydroxy-4-methylvaleric acid or 2-hydroxy-4-methylpentanoic acid, is a derivative of leucine with a molecular weight of 132.16g/mol. It is a normal constituent of human plasma as well as an animal protein fermentation product of Lactobacillus plantarum. HICA is formed by transamination of leucine to 2-ketoisocaproic acid (KICA) followed by a reduction reaction of KICA to HICA, which is the end product of the pathway. Hydroxyisocaproic acid dehydrogenase (HicDH) is required for the latter reaction . In humans, HicDH may operate in a two-directional manner, and HICA metabolism takes place mainly in muscles and the liver. However, only a few bacterial pathogens are known to express HicDH activity.

Plasmid-mediated quinolone resistance genes in enteroaggregative Escherichia coli from infants in Lima, Peru

2012-04-23

Since the description of the first horizontally transferable quinolone resistance mechanism in the late 1990s, several types of plasmid-mediated quinolone resistance (PMQR) genes have been described , including: (i) five qnr families [qnrA1–7, qnrB1–47, qnrC, qnrD and qnrS1–5 (http://www.lahey.org/qnrstudies)], encoding small pentapeptide-repeat proteins that protect type II DNA topoisomerases from quinolones; (ii) aac(6′)-Ib-cr, encoding a modified aminoglycoside acetyltransferase also active on certain fluoroquinolones; and (iii) qepA and oqxAB, encoding quinolone-specific and multidrug efflux systems, respectively. PMQR genes by themselves are able to confer only a moderate reduction in quinolone susceptibility, but they have been advocated as promoting the emergence of chromosomal mutations leading to resistance levels of clinical significance .

First report of a Pseudomonas aeruginosa clinical isolate co-harbouring KPC-2 and IMP-18 carbapenemases

2012-04-23

The Ambler class B metallo-β-lactamases such as IMP (31 IMP-like variants) and VIM (32 VIM-like variants), amongst others, and the class A Klebsiella pneumoniae carbapenemases (KPC-2 to KPC-12 variants) are broad-spectrum β-lactamases capable of inactivating most β-lactam antibiotics, including the carbapenems (http://www.lahey.org). Pseudomonas aeruginosa strain W2PA9-42, resistant to all antibiotics, was isolated from a complicated surgical patient. Polymerase chain reaction (PCR) and DNA sequencing analysis of the isolate identified both blaKPC-2 and blaIMP-18. P. aeruginosa harbouring either blaKPC or blaIMP-18 have been previously detected in Puerto Rico . Although Klebsiella spp. co-producing KPC and blaIMP-4 or blaIMP-8 have been previously reported from China , to our knowledge this is the first report of a P. aeruginosa co-harbouring KPC and IMP carbapenemases.

Sequence type 101 (ST101) as the predominant carbapenem-non-susceptible Klebsiella pneumoniae clone in an acute general hospital in Italy

2012-04-25

Klebsiella pneumoniae is one of the most common multidrug-resistant (MDR) Gram-negative organisms worldwide, responsible for high morbidity and mortality both in hospitals and alternative healthcare settings. Recently, increasing use of carbapenems has promoted the emergence and dissemination of carbapenem-non-susceptible MDR K. pneumoniae strains . In Italy, both metallo-β-lactamases belonging to the VIM type and, more recently, carbapenemases of the K. pneumoniae carbapenemase (KPC) type have been detected in these strains .

Nosocomial occurrence of OXA-48-producing enterobacterial isolates in a Moroccan hospital

2012-04-23

Carbapenems possess the most powerful in vitro activity against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae . Resistance to carbapenems is mediated mostly by two mechanisms: (i) production of a β-lactamase (a cephalosporinase or an ESBL) with no significant carbapenemase activity, combined with decreased permeability due to porin loss or alteration; or (ii) production of a carbapenem-hydrolysing β-lactamase . Carbapenemases identified in Enterobacteriaceae are either metallo-β-lactamases (IMP, VIM, NDM), plasmid-mediated clavulanic acid-inhibited β-lactamases (mostly KPC), or the class D OXA-48-type β-lactamases .