The red menace: Emerging issues in antimicrobial resistance in gram-negative bacilli

Gram-negative bacilli cause more than one third of all nosocomial infections in US hospitals. Despite a surfeit of new and highly potent antimicrobial agents, the problem of resistance in these pathogens continues to increase. Particularly important is the emergence of resistance to the fluoroquinolone and β-lactam classes of antimicrobial agents. Recent work has confirmed that resistance to fluoroquinolone antibiotics is a complex process that involves mutations in the target enzymes (topoisomerase II and IV), decreased access to the target enzyme resulting from low permeability of the outer membrane (this is primarily important in Pseudomonas aeruginosa), and active efflux from the cell. Resistance to β-lactam antibiotics, however, is primarily caused by the elaboration of an ever-growing number of β-lactamases. Our ability to understand the genetic and biochemical underpinnings of these resistance phenotypes will be an important factor in determining the ultimate success of efforts to control their emergence and spread.     

Increasing antimicrobial resistance in gram-negative bacilli isolated from patients in intensive care units

BACKGROUND: We investigated gram-negative bacilli from patients in intensive care units to determine whether antimicrobial resistance was increasing. METHODS: Minimal inhibitory concentrations were determined by broth microdilution on 334 gram-negative bacilli collected in 1990, 1995, and 1998. RESULTS: During the 3 study years, the types of gram-negative bacilli encountered in our intensive care units changed with proportional increases of Pseudomonas sp and decreases of inducible enterics. Dramatic increases in resistance for ceftazidime, cefotaxime, and piperacillin were paralleled between respiratory-tract isolates and inducible enterics. By 1998, ticarcillin was more active than piperacillin against most isolates except Escherichia coli and Klebsiella sp, and most isolates became more resistant to gentamicin and tobramycin. CONCLUSIONS: Continuous changes in the types of gram-negative bacilli and antimicrobial resistance complicate empirical selection of antimicrobials in the intensive care units. These complications will place more emphasis on communication and strategy formations among health care workers (nurses, physicians, laboratorians, and pharmacists) in an effort to treat infections in a timely and effective manner.     

Antistaphylococcal activity and beta-lactamase resistance of newer cephalosporins.

Four newer cephalosporins (cefazolin, cefamandole, SK&F 59962, and cefoxitin) were investigated for determination of their antistaphylococcal activity and relative stability to staphylococcal beta-lactamase (penicillinase). Crude preparations of beta-lactamase from recent clinical isolates of Staphylococcus aureus were used. Cefamandole and SK&F 59962 were highly active against both large and small inocula of staphylococci and were resistant to staphylococcal beta-lactamase. Cefoxitin, although resistant to beta-lactamase, possessed less antibacterial potency but was still approximately as active as methicillin. Cefazolin was somewhat more susceptible to staphylococcal beta-lactamase than the other three agents and resembled cephaloridine in this respect. With minor exceptions, a correlation was found between the susceptibility of different agents to beta-lactamase and the magnitude of the effect of inoculum size when the drugs were tested against large and small inocula of staphylococci.     

The sensitivity of gentamicin-resistant gram-negative bacilli to cefotaxime,other cephalosporins and aminoglycosides

Summary The sensitivities of 80 gentamicin-resistant gramnegative bacilli to cefotaxime, cefuroxime, cefoxitin, cefamandole, cefazolin, tobramycin, netilmicin and amikacin were determined. Amikacin was the most active aminoglycoside. However, the percentage sensitivity to cefotaxime of most of the species was higher than, or equal to, any of the other antibiotics tested. Cefotaxime was particularly active againstProvidencia spp.,Serratia spp.,Klebsiella spp., andPseudomonas maltophilia, being 16 to 256 times more active than the next best cephalosporin or cephamycin. Clinical trials of cefotaxime are now required.

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Die Empfindlichkeit von Gentamicin resistenten, gramnegativen Bakterien gegenüber Cefotaxim, anderen Cephalosporinen und Aminoglykosiden

Zusammenfassung Die Empfindlichkeit von 80 Gentamicin resistenten, gramnegativen Bakterien gegenüber Cefotaxim, Cefuroxim, Cefoxitin, Cefamandol, Cefazolin, Tobramycin, Netilmicin und Amikacin wurde bestimmt. Amikacin war das wirksamste Aminoglykosid. Jedoch war die prozentuale Empfindlichkeit gegenüber Cefotaxim bei den meisten Stämmen höher oder ebenso groß wie die der anderen untersuchten Antibiotika. Cefotaxim war besonders wirksam gegenProvidencia spp.,Serratia spp.,Klebsiella spp. undPseudomonas maltophilia, dabei war es 16- bis 256mal wirksamer als das nächst beste Cephalosporin oder Cephamycin. Klinische Untersuchungen über Cefotaxim sind jetzt vonnöten.

     

非发酵糖革兰阴性杆菌感染的治疗困境与药物选择

近年来,细菌耐药性已成为全球关注的问题.由耐药株引起的院内感染不仅延长患者的住院时间,增加医疗费用,而且危及患者的生命.     

Endemic aminoglycoside resistance in gram-negative bacilli: epidemiology and mechanisms

Isolates of gentamicin-resistant gram-negative bacilli from clinical specimens peaked at nine to 10 per month in 1973-1974. Instituting barrier-type precautions during 1974-1977 was associated with a sustained 87% reduction in resistant Enterobacteriaceae. The number of resistant Pseudomonadaceae fell temporarily by 28%, paralleling gentamicin usage. During an endemic 15-month period in 1976-1977 nonenzymatically mediated resistant Pseudomonas aeruginosa often emerged after aminoglycoside therapy in patients who had prior carriage of sensitive strains of the same serotype (P = 0.002); this resistance was associated with wound or sputum isolates (P = 0.003). Resistant Enterobacteriaceae more often demonstrated the converse, that is, spread of urinary tract isolates with enzymatically mediated resistance from patients not on aminoglycoside therapy. These findings suggest that control measures to minimize occurrence of resistant bacilli include barrier-type precautions for patients with resistant Enterobacteriaceae, evaluation of transfers and readmissions as a source of resistant organisms, and reduction of aminoglycoside use to decrease the selection of nonenzymatic resistance.     

Analysis of antimicrobial resistance among gram-negative bacilli and antimicrobial use in intensive care unit patients for 5 years in a Veterans Affairs medical center

BACKGROUND: Gram-negative bacilli antimicrobial resistance remains a significant problem for patients in the intensive care unit (ICU). Patterns of antimicrobial use may be a contributing factor. METHODS: Gram-negative bacilli from ICU patients of a Veterans Affairs (VA) medical center were tested to determine in vitro antimicrobial susceptibility (205 isolates in 1995 and 209 in 1999). Antimicrobial use was calculated from 1995 through 1999. RESULTS: For Pseudomonas aeruginosa, significant declines in susceptibility to ciprofloxacin (medical ICU [MICU] individually and all units) and aztreonam (all units) were noted. For gram-negative bacilli that was non-P aeruginosa, significant increases in susceptibility to ceftazidime (MICU, surgical ICU, and all units), gentamicin (all units), and ticarcillin/clavulanate (MICU) were noted. The most notable trends in antimicrobial usage were sharp increases in fluoroquinolone use in the MICU and surgical ICU and substantial decreases in the use of third-generation cephalosporins, monobactams, and aminoglycosides. In each instance of significant change in the susceptibility of a group of organisms to an antibiotic, there was a corresponding inverse change in the use of the antibiotic and/or its antimicrobial category (except for aztreonam). CONCLUSIONS: Significant changes in antimicrobial use may affect certain gram-negative bacilli antimicrobial susceptibilities in ICUs.     

Penetration of newer cephalosporins into cerebrospinal fluid

A review of the world literature on the penetration (ratio of concentrations of cerebrospinal fluid to concentrations of serum) and attainable antibiotic concentrations in the cerebrospinal fluid in humans for cefuroxime, cefoxitin, cefotaxime, ceftizoxime, cefmenoxime, cefamandole, cefoperazone, moxalactam, ceftazidime, and ceftriaxone indicates that, with the exceptions of cefamandole and cefoperazone, all agents appear equivalent. We conclude that the choice of cephalosporin for the treatment of acute bacterial meningitis should depend mainly on the potency of the agent for the specific meningeal pathogens in question. For the treatment of common meningeal pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) and for gram-negative bacilli, mainly Escherichia coli and Klebsiella (excluding Pseudomonas aeruginosa), the cefotaxime-ceftriaxone group of cephalosporins has accrued the most clinical experience and the most pharmacokinetic data, while for P. aeruginosa the major interest has centered on ceftazidime.     

哌拉西林-舒巴坦等七种药物对非发酵菌体外抗菌活性的研究

目的 评价哌拉西林-舒巴坦等7种药物对非发酵菌的体外抗菌活性.方法 采用微量肉汤稀释法测定哌拉西林-舒巴坦对细菌的体外抗菌作用.结果 广州地区6家医院共收集菌株770株,其中铜绿假单胞菌216株,鲍曼不动杆菌242株,嗜麦芽窄食单胞菌100株,洋葱伯克霍尔德菌119株,黄杆菌属57株,产碱杆菌属36株.对所有铜绿假单胞菌,哌拉西林-舒巴坦的敏感性最高(71.9%),而亚胺培南、头孢吡肟、头孢他啶、头孢哌酮-舒巴坦敏感性均低于50%.对亚胺培南不敏感的铜绿假单胞菌,哌拉西林-舒巴坦敏感性仍可达55.8%.对碳青霉烯敏感的鲍曼不动杆菌,哌拉西林-舒巴坦和头孢哌酮-舒巴坦敏感性最高,分别为71.0%和73.0%.对嗜麦芽窄食单胞菌,26%和20%的菌株对哌拉西林-舒巴坦和哌拉西林-他唑巴坦的最低抑菌浓度(MIC)≤16 mg/L.对洋葱伯克霍尔德菌,69%的菌株对哌拉西林-舒巴坦的MIC≤16 mg/L.对黄杆菌属和产碱杆菌属,哌拉西林-舒巴坦、头孢哌酮-舒巴坦和哌拉西林他唑巴坦3种加酶复合制剂敏感性最高,分别为70.2%、63.2%、57.9%和94.4%、94.4%、91. 7%.结论 哌拉西林-舒巴坦对多种非发酵菌尤其是碳青霉烯不敏感的铜绿假单胞菌具有良好的体外抗菌活性.     

我院近3年下呼吸道革兰阴性杆菌耐药性监测

目的 调查我院近3年下呼吸道革兰阴性杆菌的耐药情况.方法 使用MIC法对我院下呼吸道感染住院患者的痰液标本中临床分离的926株革兰阴性杆菌进行药敏试验,并用WHONET 5.4软件进行数据分析.结果 926株革兰阴性杆菌中最常见的菌种依次为大肠埃希菌(29.7%)、肺炎克雷伯菌(23.7%)、铜绿假单胞菌(14.3%)、鲍曼不动杆菌(12.1%).大肠埃希菌、肺炎克雷伯菌对多黏菌素B、亚胺培南、美罗培南和咪诺环素保持高度敏感,耐药菌率在10%以内,对阿米卡星、哌拉西林/三唑巴坦、头孢哌酮/舒巴坦、头孢他啶及头孢匹肟的耐药率为30%以内,对其余所检测药物的耐药率均在30%以上.铜绿假单胞菌对多黏菌素B和咪诺环素;而亚胺培南,美罗培南、哌拉西林/三唑巴坦,头孢哌酮/舒巴坦和阿米卡星耐药率低于30%{鲍曼不动杆菌耐药情况比较严重,只有多黏菌素B、头孢哌酮/舒巴坦高度敏感,耐药率在10%以内,对亚胺培南和美罗培南的耐药率在20%以内,对其余所检测药物的耐药率均在30%到60%以上.结论 本研究结果对我院革兰阴性杆菌感染的经验用药治疗有重要参考价值.     

Hydrolytic rate at low drug concentration as a limiting factor in resistance to newer cephalosporins

Hydrolysis kinetics of two cephalosporinases from Citrobacter freundii and Proteus vulgaris having different affinities for cefotaxime and ceftazidime was assessed in studies with cefotaxime, ceftazidime, BMY-28142, and imipenem. The two cephalosporinase genes were cloned into strains of Escherichia coli. The production of these cephalosporinases in strains of E. coli, as well as in the derepressed mutants of C. freundii and P. vulgaris, caused a decrease in susceptibility to the newer cephalosporins. The difference in the rate of hydrolysis at a 0.1 microM concentration of substrate adequately explains the difference in antibacterial activity between cefotaxime and BMY-28142 against E. coli strains with the two cephalosporinases. The results indicate that hydrolysis rate at low substrate concentration, rather than binding with beta-lactams, would be a limiting factor in resistance. The low affinity of cephalosporinases for BMY-28142 means high stability of the agent to the enzymes at low concentration. Furthermore, outer membrane permeability affects the susceptibility of E. coli to cephalosporins synergistically with hydrolysis by cephalosporinases.     

Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli.

To evaluate the potential bias of analyzing aggregated data, we separately examined antibiotic exposure and resistance data for 35,423 patients admitted to a university hospital in Utah, from both an individual-patient perspective and group-level perspective. From 1994 through 1998, use of defined daily doses (per 1000 patient-days) of fluoroquinolones, third-generation cephalosporins, ampicillin-sulbactam, and imipenem increased by 82%, 38%, and 99%, and decreased by 38%, respectively, whereas group-level resistance rates of Enterobacteriaceae or Pseudomonas species changed only minimally. However, in individual-patient-level analyses performed by multivariable proportional hazards regression, exposure to a fluoroquinolone, third-generation cephalosporin, ampicillin-sulbactam, or imipenem was a strong risk factor for resistance to fluoroquinolones (adjusted hazard ratio [AHR], 4.0; P<.001), third-generation cephalosporins (AHR, 3.5; P<.001), ampicillin-sulbactam (AHR, 2.3; P=.008), or imipenem (AHR, 5.7; P<.001), respectively. Thus, group-level and individual-patient-level analyses of antibiotic-use-versus-susceptibility relations yielded divergent results. Multicenter studies should include individual-patient-level data to elucidate more fully the relation between antibiotic exposure and resistance.     

Gentamicin resistance in gram-negative bacilli: occurrence of modifying enzymes and their influence on susceptibility testing

Among 272 gram-negative bacilli, regarded as strains with reduced susceptibility to gentamicin by the disc test, 156 strains were resistant (greater than or equal to f microgram/ml) by the agar dilution method. Altogether 76% of the 156 strains were cross-resistant to tobramycin, kanamycin, streptomycin and amikacin. Amikacin showed the highest antibacterial activity in vitro. 32 of the resistant strains produced acetylating or adenylylating enzymes, which caused resistance. The production of enzymes was not limited to any genera. Complete cross-resistance to aminoglycoside antibiotics was recorded in 45%, 98% and 22% respectively, of Pseudomonas aeruginosa, Ps. maltophilia and other gram-negative rods. Enzyme-producing strains were not cross-resistant to all aminoglycosides. Changes in MICs and inhibition zones with different inocula among enzyme-producing strains emphasize the importance of standardized inocula in susceptibility testing.