Selection of a surrogate beta-lactam testing agent for initial susceptibility testing of doripenem, a new carbapenem

Doripenem, a broad-spectrum parenteral carbapenem, has potency and pharmacokinetic/pharmacodynamic features most similar to imipenem and meropenem. Because of potential delays in release of commercial testing devices post-regulatory approval (US Food and Drug Administration), "surrogate markers" offer immediate susceptibility guidance for doripenem use. Cross-susceptibility analysis of reference MIC values compared imipenem, meropenem, and ertapenem with doripenem for 8 groupings of recent bacterial isolates (19308 strains). Use of proposed carbapenem or oxacillin surrogate testing agents until doripenem-containing commercial systems are available provides 89.1% to 100.0% absolute categorical agreement with <0.1% false-susceptible error, a level of accuracy recommending interim clinical application. Generally, isolates that are susceptible to other tested carbapenems can be considered susceptible to doripenem; however, some organisms that are intermediate or resistant to imipenem or meropenem may be susceptible to doripenem and will require additional susceptibility testing.     

Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases

BACKGROUND: Bacteria that produce extended-spectrum beta-lactamases (ESBLs) are resistant to penicillins,cephalosporins, and monobactams. The results of clinical studies suggest that the carbapenems imipenem and meropenem may be effective against bacteria that produce ESBLs, although it is not known whether the new once-daily carbapenem ertapenem or the fluoroquinolones are useful against infections caused by ESBL-producing bacteria. OBJECTIVE: The present study compared the simulated pharmacodynamics of the carbapenems imipenem,meropenem, and ertapenem; the simulated pharmacodynamics of the fluoroquinolones levofloxacin, gatifloxacin, and ciprofloxacin with those of the carbapenems; and the simulated pharmacodynamics of levofloxacin 750 mg with those of levofloxacin 500 mg, all against gram-negative isolates that did and did not produce ESBLs METHODS: Pharmacokinetic data were obtained from studies in healthy humans. Minimum inhibitory concentrationsMICs) for bacteria that did and did not produce ESBLs were determined in triplicate using broth-microdilution techniques as recommended by National Committee for Clinical Laboratory Standards guidelines. Monte Carlo simulation was used to construct pharmacodynamic models for imipenem, meropenem, ertapenem, levofloxacin, gatifloxacin, and ciprofloxacin. Pharmacodynamic measures of interest were the probability of the free concentration remaining above the MIC >-40% of the time (T>MIC > or =40%) for carbapenems and the likelihood of achieving a free AUC:MIC ratio > or =125 for fluoroquinolones. RESULTS: MICs were determined for 39 isolates that produced ESBLs and 45 isolates that did not Bacteria that did not produce ESBLs were > or =93% susceptible to all carbapenems and fluoroquinolones tested. Among bacteria that produced ESBLs, rates of susceptibility to the specific agents were as follows: imipenem, 100%; meropenem, 97%; ertapenem, 87%; levofloxacin, 54%; gatifloxacin, 44%; and ciprofloxacin, 36%. In the pharmacodynamic models, imipenem and meropenem had an equal likelihood of achieving a free T>MIC > or =40% against bacteria that produced ESBLs (> or =97%) and bacteria that did not produce ESBLs (> or =98%). In contrast, the likelihood of ertapenem achieving a free T>MIC > or =40% was lower against bacteria that produced ESBLs (78%) than against bacteria that did not produce ESBLs (94%). Similarly, the fluoroquinolones were less likely to achieve a free AUC:MIC ratio > or =125 against bacteria that produced ESBLs (2%-13%) than against bacteria that did not produce ESBLs (85%-91%). CONCLUSIONS: Carbapenems had superior in vitro activity against bacteria that produced ESBLs compared with fluoroquinolones. Pharmacodynamic modeling based on local ESBL-producing isolates and pharmacokinetic data from healthy humans indicated that imipenem and meropenem may have a greater likelihood of achieving pharmacodynamic targets against bacteria that produce ESBLs than ertapenem or fluoroquinolones.     

呼吸道感染中革兰阴性杆菌分布及耐药性变迁

目的了解徐州医学院附属医院近5年住院患者呼吸道感染分离菌中革兰阴性杆菌的分布及耐药性的变化。方法收集该院2008至2012年住院呼吸道感染患者分离菌株,进行药敏试验并分析结果。结果呼吸道标本主要来源于ICU、神经科和呼吸科;5年内大肠埃希菌所占比率呈显著下降趋势,克雷伯菌属、不动杆菌属细菌逐年升高,铜绿假单胞菌略有降低。近3年嗜麦芽窄食单胞菌增多。革兰阴性杆菌对多黏菌素B敏感率保持在90．0％以上;大肠埃希菌对碳青霉烯类抗生素敏感率保持90．0％以上;碳青霉烯类抗生素对不动杆菌属和克雷伯菌属细菌的抗菌活性逐年下降;细菌对头孢菌素类的敏感性普遍降低,大肠埃希菌和克雷伯菌属细菌对头孢菌素类抗生素敏感率〈20．0％,对氨曲南的敏感率更低;而对阿米卡星的敏感性有所恢复。结论革兰阴性杆菌是呼吸道感染的重要病原菌,对临床常用抗菌药物敏感率下降值得重视,应加强对呼吸道病原菌耐药性监测和防控。     

Comparative in-vitro activity of carbapenem antibiotics against respiratory pathogens isolated between 1999 and 2000

We investigated the antibacterial activity of 12 antibiotics, inclusive of four carbapenems, against 167 strains of respiratory pathogens isolated between 1999 and 2000. Thirty strains of methicillin-susceptible Staphylococcus aureus (MSSA), 28 strains of methicillin-resistant S. aureus (MRSA), 11 strains of penicillin-susceptible Streptococcus pneumoniae (PSSP), 29 strains of penicillin-resistant S. pneumoniae (PRSP), 30 strains of Pseudomonas aeruginosa, 14 strains of Moraxella catarrhalis, and 25 strains of Haemophilus influenzae were examined. The minimum inhibitory concentration (MICs)_50/90 (μg/ml) of imipenem, panipenem, meropenem, and biapenem against the clinical isolates obtained between 1999 and 2000 were: 0.06/0.25, 0.12/0.25, 0.12/0.25, and 0.12/0.25, respectively, against MSSA; 16/32, 16/32, 16/32, and 8/32 against MRSA; ≦0.015/0.06, ≦0.015/0.03, 0.03/0.12, and ≦0.015/0.06 against PSSP; 0.12/0.25, 0.03/0.06, 0.25/0.5, and 0.12/0.25 against PRSP; 1/8, 2/8, 0.5/2, and 2/16 against P. aeruginosa; 0.06/0.06, 0.03/0.06, ≦0.015/0.06, and 0.06/0.12 against M. catarrhalis; and 1/4, 1/4, 0.12/0.25, and 2/4 against H. influenzae. A comparison of the antibacterial activity of the four carbapenems with that found in our previous studies showed no significant difference in the susceptibility of clinical isolates, except for a slight decrease in the susceptibility of MSSA. Carbapenems have remained effective for severe infections. The MIC data showed that imipenem and panipenem were more active than meropenem and biapenem against gram-positive bacteria, and that meropenem and biapenem were more active than imipenem and panipenem against gram-negative bacteria. As only meropenem had an MIC₉₀ below the breakpoint of pneumonia against all species except MRSA, meropenem was considered to be the most potent of the four carbapenems studied. Received: February 8, 2001 / Accepted : June 5, 2001     

Clinical pharmacokinetics of meropenem and biapenem in bile and dosing considerations for biliary tract infections based on site-specific pharmacodynamic target attainment

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥ 90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥ 90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.     

1995-2004年下呼吸道感染病原菌变迁

目的了解1995—2004年湘雅医院呼吸科下呼吸道感染住院患者病原菌及其药敏变迁情况。方法对呼吸病房下呼吸道感染住院患者痰菌（或支纤镜吸取分泌物）培养阳性标本结果进行回顾性统计分析。结果分离出细菌2158株，其中革兰阴性杆菌占84．9％，病原菌主要为铜绿假单胞菌、肺炎克雷伯菌、鲍曼不动杆菌和大肠埃希菌；革兰阳性球菌占15．1％，主要病原菌为金葡菌和肺炎链球菌。20世纪90年代中后期和2000年以后相比革兰阴性杆菌有所减少，而革兰阳性球菌有所增加。药敏试验结果提示主要革兰阴性杆菌对美罗培南、头孢哌酮-舒巴坦均较敏感。铜绿假单胞菌对阿米卡星耐药率也低，对头孢噻肟、头孢曲松耐药率较高；肺炎克雷伯菌对头孢他啶也较敏感，对头孢哌酮、头孢噻肟、头孢曲松耐药率较铜绿假单胞菌低；主要革兰阳性球菌对阿奇霉素、红霉素、青霉素及克林霉素耐药率均较高。其中金葡菌对万古霉素均敏感；肺炎链球菌对美罗培南、左氧氟沙星耐药率低。结论近10年下呼吸道感染病原菌以革兰阴性杆菌为主，但有逐渐减少的趋势。主要病原菌对部分抗菌药物的耐药率有逐渐增高的趋势，临床应合理应用抗菌药，以延缓细菌耐药性的产生。     

MYSTIC program: summary of European data from 1997 to 2000.

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a global study providing in-vitro surveillance data on microbial susceptibility in centers that prescribe meropenem. This paper summarizes data on the activity of meropenem and five comparator agents against 13,793 clinical isolates from 31 centers in 10 European countries, 1997-2000. Meropenem and imipenem demonstrated broad-spectrum activity against the tested organisms, including beta-lactamase-producing strains that were co-resistant to quinolones and aminoglycosides. The carbapenems were active against the most frequently isolated pathogens including staphylococci (98-100% susceptible), Pseudomonas aeruginosa (65-82% susceptible) and Klebsiella pneumoniae (98-100% susceptible). Resistance to penicillins and cephalosporins was observed, particularly among Enterobacter species in Southern and Eastern Europe. Eastern Europe showed a high prevalence of AmpC beta-lactamase and extended-spectrum beta-lactamase-producing strains in Russia (2000); 47% and 28% of Enterobacteriaceae isolates were AmpC or ESBL-producers, respectively. There was no significant decrease in susceptibility to the carbapenems throughout the four-year period. Meropenem and imipenem appear to remain reliable options for the treatment of serious nosocomial infections.     

替加环素、米诺环素、多黏菌素B对碳青霉烯类敏感性降低和不敏感鲍曼不动杆菌体外抗菌活性

目的调查替加环素、米诺环素、多黏菌素B等对碳青霉烯类抗生素敏感性降低鲍曼不动杆菌（CDSAB）和碳青霉烯不敏感鲍曼不动杆菌（CNSAB）体外抗菌活性,为临床治疗该类菌感染提供依据。方法采用琼脂稀释法检测替加环素、米诺环素、多黏菌素B等15种抗菌药物对2002-2009年深圳市人民医院临床分离56株CDSAB（美罗培南和亚胺培南MIC=1～4mg／L）和178株CNSAB（美罗培南或亚胺培南MIC≥8mg／L）的最低抑菌浓度（MIC）,采用WHONET5．6软件分析处理数据。结果多黏菌素B对CDSAB和CNSAB体外抗菌活性最高,细菌对其均100％敏感,MIC50和MIC90均为1mg／L,其次为替加环素和米诺环素,约80％CDSAB对二者敏感或中介,MIC50／MIC90分别为4／8mg／L和8／16mg／L;约95％CNSAB对替加环素和米诺环素敏感或中介,MIC50／MIC90分别为4／4mg／L和4／8mg／L。结论多黏菌素B、替加环素和米诺环素对碳青霉烯类抗生素敏感性降低和不敏感鲍曼不动杆菌具有较强的体外抗菌活性。     

Efficacy of Humanized Carbapenem and Ceftazidime Regimens against Enterobacteriaceae Producing OXA-48 Carbapenemase in a Murine Infection Model

Enterobacteriaceae producing the OXA-48 carbapenemase are emerging worldwide, leaving few treatment options. Efficacy has been demonstrated in vivo with ceftazidime against a ceftazidime-susceptible OXA-48 isolate but not with imipenem despite maintaining susceptibility. The relationship between phenotype and in vivo efficacy was assessed for OXA-48 producers using humanized regimens of 2 g doripenem every 8 h (q8h; 4 h infusion), 1 g ertapenem q24h, 2 g ceftazidime q8h (2 h inf), and 500 mg levofloxacin q24h. Each regimen was evaluated over 24 h against an isogenic pair (wild-type and OXA-48 Klebsiella pneumoniae strains) and six clinical OXA-48 isolates with and without other extended-spectrum β-lactamases in immunocompetent and neutropenic murine thigh infection models. Efficacy was determined using the change in bacterial density versus 24-h growth controls in immunocompetent studies and 0-h controls in neutropenic studies. Bacterial reductions of ≥1 log CFU were observed with all agents for the wild-type strain. Consistent with low MICs, ceftazidime and levofloxacin exhibited efficacy against the isogenic OXA-48 strain, whereas doripenem did not, despite having a susceptible MIC; no activity was observed with ertapenem, consistent with a resistant MIC. Similar trends were observed for the clinical isolates evaluated. Ceftazidime, levofloxacin, and ertapenem efficacy against isogenic and clinical OXA-48-producing strains correlated well with phenotypic profiles and pharmacodynamic targets, whereas efficacy with doripenem was variable over the MIC range studied. These data suggest that carbapenems may not be a reliable treatment for treating OXA-48 producers and add to previous observations with KPC and NDM-1 suggesting that genotype may better predict activity of the carbapenems than the phenotypic profile.     

Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999–2008)

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a global, longitudinal antimicrobial resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of meropenem and selected other broad-spectrum comparator agents. In 1999, and from 2000 through 2008, a total of 10 or 15 United States (USA) medical centers each forwarded 200 nonduplicate clinical isolates from serious infections to a central processing laboratory. Over the 10-year period of this surveillance program, the activity of meropenem and an average of 11 other antimicrobial agents were assessed against a total of 27?289 bacterial isolates using Clinical and Laboratory Standards Institute reference methods. Meropenem consistently demonstrated low resistance rates against Enterobacteriaceae species isolates through 2008 and did not exhibit a widespread change in resistance rates over the monitored interval. In fact, the incidence of emerging carbapenemase-producing (KPC-type) Klebsiella spp. showed a decline in 2008 compared to the steeply increasing rates observed from 2004 to 2007. Moreover, the KPC serine carbapenemases have spread to other Enterobacteriaceae species monitored by the MYSTIC Program. Greatest increases in antimicrobial resistance rates were observed for the fluoroquinolones (ciprofloxacin, levofloxacin) among all species monitored by the MYSTIC Program. Current susceptibility rates for meropenem when tested against prevalent pathogens were Pseudomonas aeruginosa (439 strains, 85.4% susceptible), Enterobacteriaceae (1537 strains, 97.3% susceptible), methicillin-susceptible staphylococci (460 strains, 100.0% susceptible), Streptococcus pneumoniae (125 strains, 80.2% at meningitis susceptibility breakpoints), other streptococci (159 strains, 90.0–100.0% susceptible), and Acinetobacter spp. (127 strains, 45.7% susceptible), the widest spectrum among β-lactams tested in 2008 and throughout the last decade. Continued local surveillance of broad-spectrum agents following the completion of the MYSTIC Program (USA) appears critical to detect emerging resistances among pathogens causing the most serious infections requiring carbapenem agents.     

Contemporary activity of meropenem and comparator broad-spectrum agents: MYSTIC program report from the United States component (2005)

The Meropenem Yearly Susceptibility Test Information Collection Program is a 9-year-old antimicrobial resistance surveillance network of more than 100 medical centers worldwide, including 15 sites in the United States (US) that monitors the susceptibility of Gram-negative and Gram-positive bacterial pathogens especially to carbapenems. In 2005, the antimicrobial activity of 11 broad-spectrum agents was assessed against 2910 bacterial isolates (2493 Gram-negative and 417 staphylococci) submitted from the US medical centers to a reference laboratory using Clinical and Laboratory Standards Institute susceptibility testing methods and interpretative criteria. Meropenem continued to demonstrate 1) high potency with MIC(90) values 4- to 16-fold lower than imipenem against the Enterobacteriaceae, 2) equal activity against Pseudomonas aeruginosa, 3) 2-fold less activity compared with imipenem against Acinetobacter spp., and 4) 4- to 8-fold less activity compared with imipenem against the oxacillin-susceptible staphylococci. The wide spectrum of activity for carbapenems against Enterobacteriaceae (1657 strains) was confirmed by the overall rank order by percentage susceptibility at breakpoint criteria: imipenem (98.9%) > meropenem (98.7%) > cefepime (97.6%) > piperacillin/tazobactam (92.0%) > ceftriaxone (91.2%) > aztreonam (90.6%) > gentamicin = tobramycin (90.5%) > ceftazidime (90.4%) > levofloxacin (84.9%) > ciprofloxacin (83.9%). Against Acinetobacter spp. isolates, only tobramycin (92.0% susceptible) and carbapenems (92.0-85.6%) exhibited acceptable levels of activity. A continued increase in the resistance rate for both ciprofloxacin and levofloxacin was observed with highest rates found among indole-positive Proteae species (36.5-33.3%) and Escherichia coli (21.6-20.4%) isolates, some documented by molecular typing methods as clonally related. Ongoing surveillance of meropenem and other broad-spectrum antimicrobial agents appears warranted to monitor the potency and spectrum of activity against indicated Gram-negative and-positive pathogens causing serious infections in the hospital setting, and to detect the emergence of new or novel resistance mechanisms that could compromise clinical utility (serine and metallo-carbapenemases).     

Surveillance of bacterial resistance in Zigui People's Hospital,Hubei Province in 2014北大核心CSCD

Objective To investigate the distribution and resistance profile of bacterial pathogens isolated in Zigui People's Hospital, Hubei Province in 2014. Methods Antimicrobial susceptibility was determined by Kirby-Bauer test. The results were interpreted according to the Clinical and Laboratory Standards Institute breakpoints 2014 edition and analyzed by using WHONET 5.6. Results Of the 1 338 strains isolated, gram-negative bacteria accounted for 72.8% and gram-positive bacteria accounted for 27.2%. Overall, 30.4% of Staphylococcus aureus strains and 66.7% of coagulase negative Staphylococcus isolates were resistant to methicillin. For the Streptococcus pneumoniae strains, 64.9%, 24.3%, and 10.8% were susceptible, intermediate and resistant to penicillin, respectively. None of S. aureus and S. pneumoniae strains was found resistant to vancomycin, teicoplanin or linezolid. Only one strain of Enterococcus faecium was resistant to vancomycin. Enterobacteriaceae isolates were still highly susceptible to carbapenems. Extended spectrum beta-lactamases (ESBLs) were produced in of 58.3% of E. coli strains and 31.3% of Klebsiella isolates. Only 0 and 0.4% of E. coli isolates were resistant to imipenem and meropenem, and 1.7% of K. pneumoniae strains were resistant to imipenem and meropenem. In addition, 19.3% and 32.1% of the A. baumannii strains were resistant to imipenem and meropenem, respectively; 0.9% and 1.8% of Pseudomonas aeruginosa strains were resistant to imipenem and meropenem. Five strains were extensively-drug resistant, including A. baumannii, Citrobacter freundii, Escherichia coli, K. pneumoniae, and P. aeruginosa. Conclusions All gram-positive bacteria, excluding one strain of E. faecium, were not resistant to vancomycin, teicoplanin or linezolid. Gram negative bacilli strains were highly susceptible to carbapenems. A few carbapenem-resistant strains are emerging. © by Editorial Department of Chinese Journal of Infection and Chemotherapy.     

Susceptibility of Recent Bacterial Isolates to Cefdinir and Selected Antibiotics among Children with Urinary Tract Infections

Background: Cefdinir, an extended‐spectrum cephalosporin administered orally, is approved by the U.S. Federal Drug Administration for treatment of skin and respiratory tract infections. During the last two years at the authors' institution, this agent has been used as an off‐label treatment for urinary tract infections in children. Objectives: To evaluate antimicrobial susceptibility testing data in children to determine whether there is support for this prescribing practice. Methods: In this retrospective study (2003–2004), the authors compared the susceptibility patterns of urinary pathogens to cefdinir and selected antibiotics in children who were evaluated for urinary tract infections in an urban tertiary academic pediatric emergency department. Pathogens (community acquired vs. opportunistic or nosocomial) were categorized as susceptible, indeterminate, or resistant on the basis of antibiotic susceptibility breakpoints. The frequency of these categorizations for individual drugs was determined. Results: Seven hundred five isolates were recovered from urine during the study period. Pathogens isolated most frequently were Escherichia coli, Klebsiella spp, and Proteus spp. Of 431 isolates retained in the data set, 412 (95.6%) were susceptible to cefdinir. This rate was comparable or superior to rates observed for other antibiotics: 49.4% for ampicillin, 84.9% for trimethoprim–sulfamethoxazole, 88.4% for cefazolin, 93.3% for nitrofurantoin, 94.2% for ticarcillin–clavulanate potassium, 97.5% for gentamicin, and 97.7% for ceftriaxone. Cefdinir, however, had lower activity (64.7%) against 17 bacterial isolates categorized as opportunistic or nosocomial pathogens. Conclusions: Cefdinir provides good coverage against common pathogens responsible for urinary tract infections in children and compares favorably with other oral and parenteral antibiotics that are used in the empiric treatment of this infection.     

Respiratory tract pathogens isolated from patients hospitalized with suspected pneumonia in Latin America: frequency of occurrence and antimicrobial susceptibility profile: results from the SENTRY Antimicrobial Surveillance Program (1997-2000)

In spite of the recent medical advances, lower respiratory tract infections are still the most frequent infectious causes of mortality worldwide. The objective of this study was to determine the frequency of occurrence and antimicrobial susceptibility of bacterial isolates collected from hospitalized patients with pneumonia in Latin American medical centers during the first four years of the SENTRY Program. The five most frequently isolated species were (n/%): Pseudomonas aeruginosa (659/26.3%), Staphylococcus aureus (582/23.3%), Klebsiella pneumoniae (255/10.2%), Acinetobacter spp. (239/9.6%), and Enterobacter spp. (134/5.4%). P. aeruginosa demonstrated high rates of resistance to most of the antimicrobials tested. Against P. aeruginosa, the most active agents were meropenem (MIC(50), 1 microg/ml; 71.6% susceptible), amikacin (MIC(50), 4 microg/ml; 71.0% susceptible), and piperacillin/tazobactam (MIC(50), 16 microg/ml; 70.4% susceptible). Imipenem (MIC(50), 1 microg/ml; 84.1% susceptible) and meropenem (MIC(50), 2 microg/ml; 84.9% susceptible) were the most active agents against Acinetobacter spp. followed by tetracycline (MIC(50), 相似文献   

Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour infusion or bolus injection

The time that concentrations in serum are above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of beta-lactam antibiotics. The aim of this study was to demonstrate the T>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 28.33% +/- 11.67%, 45.89% +/- 22.90%, 57.00% +/- 24.82%, and 74.67% +/- 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 37.78% +/- 20.57%, 58.11% +/- 24.38%, 72.67% +/- 21.97%, and 93.56% +/- 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 57.89% +/- 24.26%, 72.89% +/- 22.40%, 85.56% +/- 16.42%, and 98.56% +/- 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater T>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 microg/ml for almost 60% of an 8-h interval.     

Activity of levofloxacin and ciprofloxacin against urinary pathogens.

This study compares the antibacterial activities of levofloxacin and ciprofloxacin against recently isolated urinary tract pathogens, by evaluating their MICs and MBCs in accordance with NCCLS susceptibility tests, time-kill curves and interference with bacterial adhesion to uroepithelial cells. A total of 200 clinical isolates was tested, including the species Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis. All E. coli isolates were susceptible to levofloxacin and only one was resistant to ciprofloxacin, and there were no differences between beta-lactamase-positive and -negative strains. K. pneumoniae strains resistant to ciprofloxacin were also resistant to levofloxacin. Methicillin-resistant S. aureus seemed to be less susceptible than methicillin-susceptible strains to these quinolones. S. epidermidis strains were susceptible to levofloxacin and ciprofloxacin, with the exception of two isolates. Incubation of S. aureus and E. coli with subinhibitory antimicrobial concentrations reduced their capacity to adhere to uroepithelial cells; this was statistically significant at 0.25 x MIC with respect to controls (P < 0.05). Inhibition of adhesion ranged from 36 to 43% when bacteria were incubated in the presence of 0.25 x MIC of levofloxacin and ciprofloxacin, and from 10 to 27% at 0.125 x MIC. These findings suggest that levofloxacin is an effective alternative to ciprofloxacin in the treatment of urinary tract infections and that sub-inhibitory concentrations may contribute to efficacy.     

Potency and spectrum reevaluation of cefdinir tested against pathogens causing skin and soft tissue infections: a sample of North American isolates

Cefdinir is a widely used orally administered cephalosporin for community-acquired respiratory tract infections and skin and soft tissue infections (SSTI). A total of 415 nonduplicate isolates of community-acquired SSTI (CA-SSTI) were collected from medical centers in North America and susceptibility tested against cefdinir and various compounds indicated for the treatment of CA-SSTI. The cefdinir MIC(50/90) in microg/mL/% susceptible for strains of the 7 principal CA-SSTI pathogens were: oxacillin-susceptible Staphylococcus aureus (0.5/0.5/100%), oxacillin-susceptible coagulase-negative staphylococci (0.06/0.12/100%), group A streptococci (< or =0.03/< or =0.03/100%), group B streptococci (< or =0.03/0.06/100%), viridans group streptococci (0.25/2/88%), Klebsiella spp. (0.12/1/95%), and Escherichia coli (0.25/0.5/95%). Cefdinir was the most potent oral cephalosporin tested against staphylococci and the Enterobacteriaceae species, and 8-fold to 64-fold more potent than cephalexin against these pathogens. Beta-Hemolytic streptococci was highly susceptible to cefdinir (MIC(90), < or =0.03-0.06 microg/mL), while viridans group streptococci showed slightly elevated MIC results. Cephalexin MIC values for streptococcal strains (MIC(90), 1-32 microg/mL) were 32-fold to 64-fold higher than those of cefdinir or other oral cephalosporins evaluated. Only 0.5% of all 415 recent CA-SSTI pathogens were resistant to cefdinir (MIC, > or = 4 mg/L). Cefdinir showed a spectrum and potency comparable or superior to other orally administered beta-lactams (cephalexin).     

In vitro activity of L-627, a new carbapenem.

The in vitro activity of L-627, a new parenterally administered carbapenem, was compared with those of imipenem, meropenem, FCE 22101 (a penem), ceftazidime, and ceftriaxone. L-627 was active against members of the family Enterobacteriaceae (MIC for 90% of strains tested [MIC90] ranging from 0.03 to 4 micrograms/ml). L-627 displayed activity equal to that of meropenem against Pseudomonas aeruginosa (MIC90, 2 micrograms/ml), although, as with other carbapenems, the antipseudomonal activity was reduced against D2-deficient strains. Staphylococci and streptococci were susceptible (MIC90 of 1.0 micrograms/ml for Staphylococcus aureus and 0.015 micrograms/ml for group A streptococci). L-627 also had activity against anaerobic bacteria (MIC90, 2.0 micrograms/ml for Bacteroides fragilis). Neisseria gonorrhoeae and Neisseria meningitidis were highly susceptible (MIC90, 0.06 micrograms/ml), and against the common respiratory pathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis), the MIC90s were less than or equal to 2.0 micrograms/ml. The protein binding of L-627 ranged from 13.8 to 22%, depending on the concentration. The presence of human serum had little effect on the MIC or MBC of L-627. These results suggest that L-627 merits further study in the treatment of infections caused by a wide range of pathogens.     

The Meropenem Yearly Susceptibility Test Information Collection antimicrobial susceptibility program in Spain: a 5-year analysis

The Meropenem Yearly Susceptibility Test Information Collection program is a global study providing in vitro surveillance data on antimicrobial susceptibility in centers prescribing meropenem. This study summarizes data on the activity of meropenem and 5 comparators against 4022 clinical isolates from 7 centers in Spain (1999-2003). Those bacteria intrinsically resistant to meropenem were excluded. Among Enterobacteriaceae, 100% of Enterobacter spp., Citrobacter spp., and Serratia spp. were susceptible to meropenem. Escherichia coli and Klebsiella pneumoniae susceptibilities to carbapenems were 100% and > or =98%, respectively. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were 3.8% of isolates, and all of them were susceptible to meropenem. Ciprofloxacin resistance in E. coli was around 20%. Meropenem and piperacillin/tazobactam were the most active agents against Pseudomonas aeruginosa. Acinetobacter baumannii were 61-90% susceptible to carbapenems, but only 6-21% susceptible to ciprofloxacin. In this period, around 100% of oxacillin-susceptible staphylococci were susceptible to meropenem. There was no significant decrease in susceptibility to the carbapenems throughout the 5-year period. The clinical use of meropenem in 7 Spanish centers did not increase bacterial resistance to this agent in the microorganisms evaluated.