Integrons and beta-lactamases--a novel perspective on resistance

The understanding of microbial resistance to the β-lactam class of antibiotics in the form of β-lactamases has come a long way since the early discoveries of narrow-spectrum penicillinases. Integron-borne β-lactamases co-occurring with a wide array of non-β-lactam resistance genes, particularly pose an increasing threat to the nosocomial environment, giving rise to multi-drug resistant microbes with complex resistance patterns. Selection of potent β-lactamases through the use of non-β-lactam agents may be possible through integron-mediated resistance. It has become imperative that we should continuously strive to understand these complex mechanisms of antimicrobial resistance, not only to overcome them, but to avoid them from evolving further.     

Resistant Haemophilus influenzae in community-acquired respiratory tract infections: a role for cefixime

An increase in Haemophilus influenzae resistance has been documented around the world during the last 30 years. Resistance is due to the production of β-lactamases, and/or changes to penicillin-binding protein (PBP) targets. The resistance problem has led to the need for new therapeutic strategies aimed at maintaining effective management of both upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs). Among antimicrobial agents tested, third-generation cephalosporins have been shown to possess excellent in vitro activity against β-lactamase-positive and -negative isolates, corresponding with proven clinical efficacy in a wide range of RTIs. The role of H. influenzae in RTIs is outlined, changing trends in epidemiological surveillance studies monitored and implications for therapy, based upon results of clinical trials discussed.     

The role of beta-lactamase producing bacteria and bacterial interference in streptococcal tonsillitis

The causes of penicillin failure in eradicating group A β-haemolytic streptococcal pharyngo-tonsillitis are described. The mechanisms accounting for the failure include the presence in the tonsils of β-lactamase producing bacteria and the absence of bacterial interference. The use of antimicrobials that can overcome and modulate these two phenomena and achieve better cure of the infection is described.     

Bactericidal activity of oral beta-lactam antibiotics in plasma and urine versus isogenic Escherichia coli strains producing broad- and extended-spectrum beta-lactamases

Bacteria harbouring extended-spectrum β-lactamases (ESBLs), derived by mutation from TEM-1, TEM-2 or SHV-1 β-lactamases, have been described world-wide. The in vitro activities of these enzymes against β-lactam antibiotics, including oral cephalosporins, are well recognised. The aim of this investigation was to assess the bactericidal activity of oral β-lactam antibiotics available in Croatia (amoxicillin/clavulanate, cephalexin, cefuroxime, cefadroxil and ceftibuten), in biological fluids against isogenic Escherichia coli strains producing broad-spectrum (TEM-1, TEM-2 and SHV-1) and extended-spectrum β-lactamases (SHV-2, SHV-3, SHV-4, SHV-5, SHV-12). Bactericidal activity of oral β-lactams in plasma and urine was tested in time-kill experiments and by determining bactericidal titres at different time intervals post-dose. The killing rate of antibiotics in urine was slower than in plasma, but faster than in Mueller–Hinton broth. High bactericidal titres in urine were only maintained throughout the whole dosing interval by ceftibuten against strains producing broad-, SHV-2 and SHV-3 β-lactamases. The older generation cephalosporins can be considered for the therapy of urinary tract infections caused by E. coli harbouring TEM-1, TEM-2 and SHV-1 β-lactamases but a shorter dosing interval is needed. Ceftibuten can be recommended with caution in ESBL producing E. coli except those producing SHV-4, SHV-5 and SHV-12 that confer resistance to it. If these enzymes are produced, fluoroquinolones or carbapenems could be considered.     

The indirect pathogenicity of Stenotrophomonas maltophilia

Stenotrophomonas maltophilia has at least two inducible β-lactamases, L1 and L2, which can hydrolyze almost all classes of β-lactam antimicrobial agents. This study was done to verify the indirect pathogenicity of S. maltophilia that could promote the growth of other β-lactam agent-susceptible bacteria in a mixed culture. We counted CFU of β-lactam agent-susceptible bacteria under the presence of imipenem or ceftazidime in a pure culture and mixed culture with S. maltophilia. Our results showed that β-lactamase leaking from S. maltophilia can encourage the growth of Serratia marcescens and Pseudomonas aeruginosa even if imipenem or ceftazidime was supplemented. This study discovered a blind spot in chemotherapy against an indirect pathogen such as S. maltophilia.     

First description of CTX-M beta-lactamase-producing clinical Escherichia coli isolates from Egypt

We studied the presence of β-lactamases with an extended spectrum of activity in clinical Escherichia coli isolates from Cairo, Egypt. Forty-six E. coli isolates were collected from patients with urinary tract infections at a university hospital in 2001. Phenotypic characterisation identified a very high extended-spectrum β-lactamase (ESBL) rate of 60.9%. Pulsed-field gel electrophoresis and plasmid profiles revealed eight different clonal groups. All ESBL producers were polymerase chain reaction-positive for bla_TEM and bla_CTX-M genes. Within the CTX-M family, three different enzymes, CTX-M-14, CTX-M-15 and CTX-M-27, were found. The ESBL producers carried multiple plasmids and further plasmid-encoded resistances. In several strains, genes for up to six aminoglycoside-modifying enzymes were detected. A linkage to fluoroquinolone resistance was not observed. This study confirms the high rate of ESBLs in Egypt and further demonstrates the worldwide spread of genes coding for CTX-M enzymes in clinical isolates.     

Inhibition of ampicillin-induced emergence of resistance in intestinal coliforms by targeted recombinant beta-lactamase

The aim of the present study was to determine whether oral targeted recombinant β-lactamase (TRBL) administration could overcome the development of ampicillin-induced resistance in the gut microbiota. Eighteen laboratory beagles with permanent jejunal fistula were randomised to receive ampicillin + placebo, ampicillin + TRBL or placebo. A total of 982 coliform isolates, collected from jejunal and faecal samples before, during and after the treatment were tested against nine antimicrobials. The proportion of ampicillin resistance (multi-resistance) among coliform isolates increased from 20 to 36% in the ampicillin + placebo group but far less, 20–36%, in the ampicillin + TRBL group. These results indicate that TRBL may prevent the emergence of β-lactam-associated resistance in coliforms in the gut.     

beta(3)-Adrenoceptor agonists: potential,pitfalls and progress

β₃-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. β₃-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, β₃-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify β₃-adrenoceptor agonist drugs because the pharmacology of both β₃- and β₁-adrenoceptors can vary; near absolute selectivity is needed to avoid β_1/2-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. β₃-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling.     

The rat lipolytic β-adrenoceptor: Studies using novel β-adrenoceptor agonists

EC₅₀ and relative intrinsic activity values were obtained for isoprenaline, fenoterol, salbutamol, prenalterol and three new β-adrenoceptor agonist, BRL 2841, BRL 35113 and BRL 35135 on rat white adipocyte lipolysis, rat atrial rate and tension, rat uterus tension and guinea-pig tracheal tension. Fenoterol and salbutamol were selective for tracheal and uterine responses, prenalterol was selective for atrial responses, but BRL 28410, BRL 35113 and BRL 35135 were selective for the adipocyte lipolytic response. pA₂ values for propratolol, ICI 118,551 and sotalol were obtained on adipocytes, atria and trachea. pA₂ values for propranolol and sotalol were much lower on adipocytes than on atria or trachea. The pA₂ value for practolol was lower on adipocytes than on atria and the pA₂ value for ICI 118,551 was lower on adipocytes than on trachea. Both agonist and antagonist studies therefore suggest that the rat adipocyte lipolytic receptor does not fit into the current β₁/β₂-adrenoceptor classification.     

Extended-spectrum beta-lactamases in Shigella flexneri from Argentina: first report of TOHO-1 outside Japan

A 9-year nation wide survey of the presence of extended-spectrum β-lactamases (ESBLs) in Shigella flexneri is described. Ten of 9033 (0.1%) isolates produced ESBLs, which were characterized by isoelectric focusing, PCR and DNA sequencing. These were CTX-M-2 (five isolates), TOHO-1 (one isolate), SHV-2 (two isolates) and PER-2 (two isolates, the first report in S. flexneri world wide). The emergence of each ESBL type in S. flexneri was not restricted to a particular region of Argentina. TOHO-1 showed a more basic isoelectric point (8.4) than that previously found (7.8) and its encoding gene (bla_TOHO-1a) harboured a silent change, G825A, relative to the reported bla_TOHO-1. All the ESBL-encoding genes were transferred to Escherichia coli by conjugation. PFGE analysis indicated that the 10 ESBL-producing S. flexneri isolates were subtypes of a unique clone.     

Antibiotic resistance mechanisms in bacteria of oral and upper respiratory origin

Over the past 20 years, antibiotic resistance has increased in virtually every species of bacteria examined. In this paper, the main mechanisms of antibiotic resistance currently known for antibiotics used for treatment of disease caused by oral and upper respiratory bacteria will be reviewed, with an emphasis on the most commonly used antibiotics. The possible role that mercury, which is released from silver amalgams, plays in the oral/respiratory bacterial ecology is also discussed, as it relates to possible selection of antibiotic resistant bacteria.     

beta-Lactam susceptibility patterns and investigation of cephalosporin hydrolysing beta-lactamases of Gram-negative extraintestinal clinical isolates

Of more than 3500 isolates of enterobacteriaceae, 48–69% were resistant to aminopenicillins and 11–45% to amoxycillin+clavulanic acid. Resistance to second and third generation cephalosporins was present in 11–17 and 3–8% of Escherichia coli, 47–56 and 15–52% of Klebsiella–Enterobacter, 36–57 and 16–27% of Proteus, Providencia and Morganella isolates. Pseudomonas aeruginosa strains varied in their resistance to antipseudomonal β-lactams. Isoelectric points, inhibitor profiles and substrate profiles of β-lactamases extracted from representatives of the resistant strains indicated that the resistance was mainly due to the hyperproduction of chromosomally encoded AmpC β-lactamases. This was confirmed by plasmid profile and PCR investigations. Extended-spectrum β-lactamase and metallo-penicillinase producing strains were not found. One Pseudomonas maltophilia strain produced an oxacillinase.     

A study of anti-inflammatory activity of some novel alpha-amino naphthalene and beta-amino naphthalene derivatives

In the present study, some naphthalene derivatives have been synthesized by incorporating azetidinyl and thiazolidinyl moieties at its alpha- or beta-positions such as alpha-(3-chloro-2-oxo-4-substituted)aryl-1-azetidinyl)naphthalenes 6-10, alpha-((substituted)aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 11-15, beta-(3-chloro-2-oxo-4-substituted aryl-1-azetidinyl)naphthalenes 21-25, and beta-(substituted aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 26-30. These compounds have also been screened for acute toxicity and anti-inflammatory and analgesic activities. Compounds which showed better anti-inflammatory and analgesic activities were also examined for their ulcerogenic liability and underwent a cyclooxygenase assay. Two compounds, 12 and 28, were found to exhibit potent anti-inflammatory activity as compared to the standard drugs phenylbutazone and naproxen.     

抗阻力运动结合有氧运动对2型糖尿病患者生理指标的影响

目的通过检测2型糖尿病患者生理指标的变化,探讨有氧运动结合抗阻力运动对2型糖尿病患者的影响。方法将80例确诊为2型糖尿病的患者随机分成实验组和对照组。对照组给予为期3个月的有氧运动,实验组在有氧运动的基础上再结合抗阻力运动,测量患者的体重、腰围、臀围、身体质量指数（BMI）、糖基化血红蛋白（AIC）、血高密度脂蛋白（HDL）、血低密度脂蛋白（LDL）、总胆固醇（TC）、三酰甘油（TG）值。结果治疗后实验组与对照组患者的体重、腰围、臀围、BMI、AIC、LDL、TC、TG值均有明显改善（均P〈0.05）;实验组患者上述指标明显优于对照组（均P〈0.05）。结论有氧运动结合抗阻力运动以及单纯有氧运动均能改善2型糖尿病患者血脂代谢及血糖控制水平,起到减肥、降血脂的作用。有氧运动结合抗阻力运动效果更佳。     

Centrally administered ß;-endorphin produces prolonged changes in δ-opioid ligand activity in vivo

Spontaneous reflex bladder contractions were recorded isometrically in urethane anesthetized rats. Bladder contractions were depressed by intracerebroventricular injections of the μ-opioid receptor agonist [D-A'la²,MePhe⁴,Gly(ol)⁵]enkephalin (DAGO) and the δ-agonist [2D-penicillamine,5D-penicillamine]enkephalin (DPDPE) respectively. The effect of DPDPE was selectively antagonized by ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH; Aib = -aminoisobutyric acid). However following the administration of β-endorphin the antagonistic action of ICI 174,864 could no longer be observed. In addition ICI 174,864 exhibited agonistic activity following β-endorphin and the effects of DPDPE were prolonged in a dose related manner by β-endorphin. These observations suggest that β-endorphin may produce complex changes in central δ-opioid receptor activity.     

The effect of bromoacetylalprenololmentane on rat atrial tension development and β-adrenoreceptors

In isolated rat atria, 1 μM bromoacetylalprenololmentane shifted the tension development curve for isoproterenol to the right of the control curve. After a 2 h washout period, no significant recovery of the isoproterenol concentration-response curve had occurred. Pretreatment of rat atrial membranes with 1 μM bromoacetylalprenololmentane resulted in an 83% decrease in the concentration of β-adrenoceptors with no change in the K_D value for [¹²⁵I]iodocyanopindolol binding to the receptors left. The results indicated that bromoacetylalprenololmentane was an irreversible β-blocker.     

Enhancement of the antibacterial activity of ampicillin by liposome encapsulation

This study showed that encapsulation of ampicillin (Amp) in liposomes prepared with synthetic lecithins enhanced its antibiotic activity against both Amp-sensitive and Amp-resistant Escherichia coli. This was demonstrated by growth inhibition of E. coli in the presence of the liposomal preparations containing Amp. Growth inhibition was also seen in the presence of exogenous β-lactamase. Adsorption of Amp onto the surface of the liposomes did not result in enhanced activity of the drug against E. coli. The encapsulation efficiency of Amp in liposomes prepared by the Bangham method (BM) was greatly affected by the phospholipids used. The efficiency increased with a rise in the phase transition temperature (T_c) of the phospholipid, the maximum encapsulation of Amp being obtained with distearoylphosphatidylcholine (DSPC). The entrapment efficiency of Amp with the reverse phase evaporation method (REV) was largely superior to that with the BM method. Kinetic studies using DSPC liposomes prepared by the REV and BM protocols demonstrated that Amp-loaded liposomes contained 60 and 72% of drug, respectively, after 24 h at 37°C.     

The alpha (1D)-adrenoceptor antagonist BMY 7378 is also an alpha (2C)-adrenoceptor antagonist

1 We have investigated the actions of the alpha(1D)-adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at alpha(1)- and alpha(2)-adrenoceptors. 2 In rat aorta (alpha(1D)-adrenoceptor), BMY 7378 (pA(2) of 8.67) was about 100 times more potent than yohimbine (pA(2) of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein (alpha(2C)-adrenoceptor), BMY 7378 (pA(2) of 6.48) was approximately 10 times less potent than yohimbine (pA(2) of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 mum) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional alpha(2D)-adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for alpha(2C)-adrenoceptors (pK(i) of 6.54) over other alpha(2)-adrenoceptors. 6 It is concluded that BMY 7378, in addition to alpha(1D)-adrenoceptor selectivity in terms of alpha(1)-adrenoceptors, shows selectivity for alpha(2C)-adrenoceptors in terms of alpha(2)-adrenoceptors.     

小儿腹部感染需氧菌菌群分布及其耐药性研究

目的:观察小儿腹部感染需氧菌菌群分布及对抗生素的耐药状况。方法:选择腹部感染性疾病的患儿684例,在手术中采集腹水标本进行常规需氧菌培养和药敏试验。结果:684例中培养阳性467例,共检出需氧菌518株:其中大肠埃希菌376株(72.6%),克雷伯菌属35株(6.8%),肠杆菌属32株(4.2%),变形杆菌27株(5.3%)。铜绿假单胞菌12株(2.3%),肠球菌22株(4.2% ) ,其它14株(2.7%)。大肠埃希菌、克雷伯菌属、变形杆菌对氨苄青霉素的耐药率达78%～94%;对庆大霉素为43%～68%,而对丁胺卡那霉素仅为4%～16%;对第一代头孢菌素及第二代头孢菌素的耐药率为13%～51%,对第三代头孢菌素耐药菌株很少;对亚胺培南`万古霉素几乎无耐药菌株。铜绿假单胞菌对亚胺培南、丁胺卡那霉素、头孢他啶的耐药率<8%。结论:条件致病菌感染和内源性感染是小儿腹部感染的特点,由于耐药性增加,腹部感染旧“金三联”方案(氨苄青霉素加庆大霉素加灭滴灵)应被其它敏感抗生素替代,如第三代头孢菌素加丁胺卡那霉素加灭滴灵     

Signaling by insulin-like growth factor 1 in brain

The homologous insulin and insulin-like growth factor (IGF) receptors are both expressed in the brain, in overlapping but distinct neuroanatomical patterns. In contrast to insulin, IGF1 is also highly expressed within the brain and is essential for normal brain development. IGF1 promotes projection neuron growth, dendritic arborization and synaptogenesis. IGF1 acts in an autocrine and/or paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3K)/Akt, also known as protein kinase B (PKB)/glycogen synthase kinase 3β (GSK3β) pathways similar to insulin signaling in peripheral tissues. IGF1 promotes neuronal survival during normal brain development mainly in hippocampal and olfactory systems that depend on postnatal neurogenesis. IGF1's anabolic and neuroprotective roles may be coordinated by inhibition of GSK3β. The identification of GSK3β as a major target of brain IGF1 signaling provides a unifying pathway for IGF1's well-established anabolic and anti-apoptotic functions, with IGF1-induced inhibition of GSK3β triggering multifaceted anabolic and neuroprotective effects.