Ampicillin-sulbactam is commonly used as an empirical therapy for invasive infections where Escherichia coli is a potential pathogen. We evaluated the clinical and microbiologic characteristics of bloodstream infection due to E. coli , with focus on cases that were nonsusceptible to ampicillin-sulbactam and not producing extended-spectrum (cid:1) -lactamase (ESBL). Of a total of 357 unique bacteremic cases identified between 2005 and 2008, 111 (31.1%) were intermediate or resistant to ampicillin-sulbactam by disk testing. In multivariate analysis, a history of liver disease, organ transplant, peptic ulcer disease, and prior use of ampicillin-sulbactam were independent risk factors for bloodstream infection with ampicillin-sulbactam-nonsusceptible E. coli . Among cases that received ampicillin-sulbactam as an empirical therapy, an early clinical response was observed in 65% (22/34) of susceptible cases but in only 20% (1/5) of nonsusceptible cases. Among 50 ampicillin-sulbactam-resistant isolates examined, there was no clonal relatedness and no evidence of produc- tion of inhibitor-resistant TEM (IRT). Instead, the resistance was attributed to hyperproduction of TEM-1 (cid:1) -lactamase in the majority of isolates. However, promoter sequences of bla TEM-1 did not predict resistance to ampicillin-sulbactam. While the plasmid copy number did not differ between representative resistant and susceptible isolates, the relative expression of bla TEM-1 was significantly higher in two of three resistant isolates than in three susceptible isolates. These results suggest high-level bla TEM-1 expression as the predominant cause of ampicillin-sulbactam resistance and also the presence of yet-unidentified factors promoting overex- pression of bla TEM-1 in these isolates. catheter at the time of infection. The Apache (cid:2)(cid:2) score (19) and modified McCabe-Jackson classification (27) were used to assess severity of illness and prognosis, respectively. An immunocom- promised state was defined as the presence of diabetes mellitus, neutropenia, or HIV infection, or receipt of steroids or other immunosuppressive therapy in the last 30 days. Clinical outcome measures. Patients with bacteremia due to E. coli were monitored after the onset of bacteremia to assess early clinical response at 96 h and 28-day mortality in response to antimicrobial therapy. Empirical antibiotic therapy was defined as administration of an antibiotic with in vitro activity against E. coli for at least 48 of the first 96 h after the first positive blood culture. Early clinical response was defined by all of the following occurring before or at 96 h from the time of first positive blood culture for a continuous 24-hour period: (i) temperature from 36.0 to 37.9°C, (ii) white blood cell count of 4,000 to 10,900/ (cid:3) l, (iii) no requirement for vasopressors, and (iv) systolic blood pressure of greater than 90 mm Hg. A case was documented as clinical failure when any of these criteria was not met. The primary endpoints of the study were clinical response at 96 h and mortality during the 28-day period after the first blood culture positive for E. coli . Susceptibility testing. For all available case-defining E. coli isolates, susceptibility testing was conducted using the disk diffusion method for ampicillin, am- picillin-sulbactam, amoxicillin-clavulanic acid, ticarcillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, cephalothin, cefoxitin, cefuroxime, cefpodoxime, ceftazidime, cefotaxime, sulfamethoxazole-trimethoprim, gentami-cin, and ciprofloxacin (BD, PCR-based Transformation of plasmids mediating ampicillin-sulbactam resistance. Plasmids were extracted from the study isolates using the alkaline lysis method as previously described (34) and transformed into E. coli DH10B by electropora-tion. Transformants were selected on LB agar containing 50 (cid:3) g/ml of ampicillin (Sigma-Aldrich, St. MO). The transformants underwent susceptibility testing as well as PCR analysis to confirm transfer of the bla TEM gene. PFGE. The study isolates were subjected to pulsed-field gel electrophoresis (PFGE) to evaluate for clonality. Genomic DNA was prepared as described previously digested with XbaI (New England Biolabs, Ipswich, MA), and subjected to electrophoresis using a CHEF III system (Bio-Rad, Hercules, CA) at 6 V with pulse time of 2.2 to 54.2 s and linear ramping at 14°C for 22 h. lambda ladder England Biolabs, was used as the DNA size marker. The relatedness of PFGE patterns was determined by the unweighted-pair group method using average linkages and the DICE setting clustering analysis on the Bionumerics software version 4.0 (Applied Maths, Sint-Martens-Latem, The results were interpreted based on the criteria described by Tenover et

Antimicrobial resistance by common respiratory tract pathogens remains a global concern, but surveillance programs allow us to recognize trends in susceptibility that may help guide empiric antimicrobial selection. During 2003 to 2004, the Global Landscape On the Bactericidal Activity of Levofloxacin (GLOBAL) surveillance program collected 9323 isolates of Streptococcus pneumoniae, 5828 isolates of Haemophilus influenzae, and 1878 isolates of Moraxella catarrhalis from 15 countries worldwide, and tested them for susceptibility to commonly used antimicrobial agents at a central laboratory. For S pneumoniae, penicillin (oral) susceptibility ranged from 41.5% (Asia) to 75.3% (Europe), while susceptibility to erythromycin ranged from 23.7% (Asia) to 87.0% (Central and South America). Susceptibility to levofloxacin was > or = 98.0% for each region studied, with the minimum inhibitory concentration (90%) (MIC(90)) = 1 microg/mL. Susceptibility to ciprofloxacin was > or = 81% for each region studied, with the MIC(90) = 2 microg/mL. For H influenzae, resistance to ampicillin ranged from 8.7% (South Africa) to 29.6% (Asia), while resistance to trimethoprimsulfamethoxazole ranged from 15.3% (United States) to 40.3% (Asia). Moraxella catarrhalis isolates from each region were > 95.0% susceptible to all antimicrobials tested. Susceptibility of H influenzae and M catarrhalis to levofloxacin was > 99.0% in each country. In general, S pneumoniae resistance to penicillin and macrolides remains a concern. Although the prevalence of ss-lactamase production by H influenzae and M catarrhalis can be high, these organisms continue to be susceptible to several commonly used antimicrobials. Respiratory fluoroquinolones continue to show high activity against these 3 organisms. There has been no change in the levofloxacin MIC(90) values for S pneumoniae and only rarely have resistant isolates of H influenzae and M catarrhalis been identified worldwide.

Although continuing care is strongly related to positive treatment outcomes for substance use disorder (SUD), participation rates are low and few effective interventions are available. In a randomized clinical trial with 150 participants (97% men), 75 graduates of a residential Veterans Affairs Medical Center SUD program who received an aftercare contract, attendance prompts, and reinforcers (CPR) were compared to 75 graduates who received standard treatment (STX). Among CPR participants, 55% completed at least 3 months of aftercare, compared to 36% in STX. Similarly, CPR participants remained in treatment longer than those in STX (5.5 vs. 4.4 months). Additionally, CPR participants were more likely to be abstinent compared to STX (57% vs. 37%) after 1 year. The CPR intervention offers a practical means to improve adherence among individuals in SUD treatment.

Objective: To review data to determine why pneumococcal isolates appear to be increasingly resistant to cefotaxime, historically regarded as having the same in vitro susceptibility to ceftriaxone, and what this observation might imply clinically. Data Sources: Literature was accessed through MEDLINE (1966–October 2007) using the MeSH terms cefotaxime, ceftriaxone, susceptibility, microbial sensitivity tests, antibiotics, pneumococcal infections, Streptococcus pneumoniae. resistance, and cephalosporin resistance. Abstracts and surveillance databases were reviewed and unpublished data were provided by state departments of health and institutions. Study Selection and Data Extraction: All articles published in the English language that were identified from the data sources were evaluated. Data Synthesis: An experimental model of pneumococcal infection in mice conducted 2 decades ago predicted that the delta T minimum inhibitory concentration (MIC) varied less for ceftriaxone than for cefotaxime. Studies of plasma and serum concentrations show that ceftriaxone remains at a concentration above the S. pneumoniae MIC for 100% of the dosing interval al 12 hours. Types of MIC susceptibility test methods for ceftriaxone and cefotaxime used against S pneumoniae respiratory isolates were found to be similar. Data from state and county health departments found microbiological discrepancies between ceftriaxone and cefotaxime. In areas with high rates of penicillin-resistant S. pneumoniae (PRSP), isolates were twice as susceptible to ceftriaxone versus cefotaxime. Surveillance databases consistently show differences between susceptibility of S. pneumoniae to cefotaxime versus ceftriaxone over time. MIC and pulsed-field gel electrophoresis studies suggest that phenotypic discrepancies may account for ponicillin resistance. Ongoing studies are examining S. pneumoniae isolates at the molecular level to determine the basis of difference in resistance to cefotaxime and ceftriaxone. Conclusions: An increase in rates of PRSP and differences in S. pneumoniae isolate susceptibility between ceftriaxone and cefotaxime emphasize the necessity for hospital laboratories to detect these changes as they occur. Clinicians should select the most appropriate agent for patients with S. pneumoniae.

Surveillance initiatives to track Streptococcus pneumoniae resistance trends are important for understanding the current in vitro effectiveness of available antimicrobial agents. The antimicrobial susceptibility profiles of S. pneumoniae (n=1479 isolates) collected from 17 geographical areas across the USA (2003-2004) were analysed; 36.8% of isolates were resistant to one or more agents (24.4% were multidrug-resistant, i.e. resistant to two or more antimicrobial classes). Multidrug resistance involved resistance to beta-lactams, macrolides, tetracycline and trimethoprim/sulphamethoxazole, but rarely fluoroquinolones (>96% of multidrug-resistant isolates were fluoroquinolone-susceptible). Multidrug resistance rates were prominent regardless of the geographical region surveyed. As this trend continues, the empirical therapeutic options for S. pneumoniae infections will diminish and there will be an ongoing need to evaluate the effectiveness of potent fluoroquinolones such as gemifloxacin.

Abstract Background Globally ICUs are encountering emergence and spread of antibiotic-resistant pathogens and for some pathogens there are few therapeutic options available. Methods Antibiotic in vitro susceptibility data of predominant ICU pathogens during 2000–2 were analyzed using data from The Surveillance Network (TSN) Databases in Europe (France, Germany and Italy), Canada, and the United States (US). Results Oxacillin resistance rates among Staphylococcus aureus isolates ranged from 19.7% to 59.4%. Penicillin resistance rates among Streptococcus pneumoniae varied from 2.0% in Germany to as high as 20.2% in the US; however, ceftriaxone resistance rates were comparably lower, ranging from 0% in Germany to 3.4% in Italy. Vancomycin resistance rates among Enterococcus faecalis were ≤ 4.5%; however, among Enterococcus faecium vancomycin resistance rates were more frequent ranging from 0.8% in France to 76.3% in the United States. Putative rates of extended-spectrum β-lactamase (ESBL) production among Enterobacteriaceae were low, <6% among Escherichia coli in the five countries studied. Ceftriaxone resistance rates were generally lower than or similar to piperacillin-tazobactam for most of the Enterobacteriaceae species examined. Fluoroquinolone resistance rates were generally higher for E. coli (6.5% – 13.9%), Proteus mirabilis (0–34.7%), and Morganella morganii (1.6–20.7%) than other Enterobacteriaceae spp (1.5–21.3%). P. aeruginosa demonstrated marked variation in β-lactam resistance rates among countries. Imipenem was the most active compound tested against Acinetobacter spp., based on resistance rates. Conclusion There was a wide distribution in resistance patterns among the five countries. Compared with other countries, Italy showed the highest resistance rates to all the organisms with the exception of Enterococcus spp., which were highest in the US. This data highlights the differences in resistance encountered in intensive care units in Europe and North America and the need to determine current local resistance patterns by which to guide empiric antimicrobial therapy for intensive care infections.

The Performance Standards for Antimicrobial Susceptibility Testing, Twelfth Informational Supplement, M100-S12, published by the National Committee for Clinical Laboratory Standards (NCCLS) in January 2002 introduced distinct minimum inhibitory concentration (MIC) interpretative breakpoints for ceftriaxone, cefotaxime, and cefepime for nonmeningeal isolates of Streptococcus pneumoniae. Previously, a single set of interpretative breakpoints was used for both meningeal and nonmeningeal isolates.

Antimicrobial resistance patterns among the principal bacterial pathogens from infections of the respiratory tract, blood, skin and soft tissue, and urinary tract of pediatric patients from the USA, Canada, Germany, France, and Italy were studied using the The Surveillance Network (TSN) database. Among Streptococcus pneumoniae isolates from respiratory tract infections, the prevalence of high-level penicillin resistance (MIC≥2 μg/ml) ranged from 1.1 (Italy) to 36.2% (USA); erythromycin resistance was higher, ranging from 13.4 (Germany) to 63.8% (France). The prevalence of β-lactamase-positive Haemophilus influenzae among isolates from lower respiratory tract infections ranged from <10 (Italy and Germany) to 38.4% (USA). Among isolates from blood and skin and soft tissue infections, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) ranged from 7.2% (Canada and Germany) to 27.3% (Italy). The prevalence of Escherichia coli and Klebsiella pneumoniae with putative extended-spectrum β-lactamases among isolates from blood, urinary tract, and skin and soft tissue infections ranged from 0 (Germany and France) to 29.6% (Italy). With the exception of pseudomonal infections or infections with MRSA, amoxicillin-clavulanate retained moderate activity, whilst ceftriaxone and cefepime were the most effective broad-spectrum injectable agents. Meropenem was the most effective agent against Pseudomonas aeruginosa with <5% resistance. Low levels of resistance, along with acceptable safety profiles and the availability of convenient oral formulations, continue to support the use of ceftriaxone, cefepime, amoxicillin-clavulanate, and meropenem as viable options for the treatment of infections in pediatric patients.

Bacterial infections of the central nervous system, especially acute infections such as bacterial meningitis require immediate, invariably empiric antibiotic therapy. The widespread emergence of resistance among bacterial species is a cause for concern. Current antibacterial susceptibility data among central nervous system (CNS) pathogens is important to define current prevalence of resistance.

SOCIETY OF CRITICAL CARE MEDICINE 34TH CRITICAL CARE CONGRESS PHOENIX, ARIZONA, USA JANUARY 15-19, 2005: Poster Presentation: Clinical Science: Sepsis/Inflammation/Infection/Antimicrobial Agents (Adult) II

Bloodstream infections are associated with significant patient morbidity and mortality. Antimicrobial susceptibility patterns should guide the choice of empiric antimicrobial regimens for patients with bacteremia.

OBJECTIVE:To assess the current (2001) activity of respiratory fluoroquinolones and comparator agents against respiratory pathogens isolated in European countries.METHODS:During 2000-2001, we prospectively collected 1995 isolates of Haemophilus influenzae, 1870 isolates of Streptococcus pneumoniae and 649 isolates of Moraxella catarrhalis from hospital laboratories in France, Germany, Greece, Italy, Spain and the UK. National Committee for Clinical Laboratory Standards (NCCLS)-approved broth microdilution antimicrobial susceptibility testing methods and interpretive criteria were used throughout.RESULTS:Of the S. pneumoniae isolates, 99.6% were susceptible to moxifloxacin, gatifloxacin and levofloxacin; the corresponding figure for H. influenzae was 100%. All M. catarrhalis isolates had moxifloxacin MICs </= 0.12 mg/L. For all three pathogens, fluoroquinolone susceptibility remained unchanged from the previous 1997-98 study. The incidence of penicillin non-susceptibility in the S. pneumoniae isolates tested remained similar to or higher than that recorded in previous studies: France, 165/291 (56.7%); Germany, 46/506 (9.1%); Greece, 20/55 (36.4%); Italy, 45/364 (12.4%); Spain, 146/268 (54.5%); and the UK, 26/386 (6.7%). Significant levels of resistance to oral compounds (cefuroxime, cefaclor, cefdinir, clarithromycin, azithromycin, tetracycline, and trimethoprim-sulfamethoxazole) were detected among S. pneumoniae isolates. beta-Lactamase production among H. influenzae isolates ranged from 6.2% to 33.1% per country, and ampicillin, clarithromycin or trimethoprim-sulfamethoxazole resistance were the most common phenotypes detected. beta-Lactamase production among M. catarrhalis isolates ranged from 94.1% to 100% per country.CONCLUSIONS:With the exception of a few localized reports, resistance to moxifloxacin and other new fluoroquinolones in common respiratory pathogens is a rare occurrence, despite significant resistance to other compound classes. Surveillance will play a key role in tracking changes in fluoroquinolone susceptibility in European countries.

The in vitro antimicrobial susceptibility of the respiratory pathogens Streptococcus Pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis to commonly tested and prescribed agents was investigated during 1999-2000 and compared with results obtained during a previous 1997-1998 study. Of 448 isolates of S. Pneumoniae collected and tested in 1999-2000, 77.2% were susceptible, 19.9% were intermediate, and 2.9% were resistant to penicillin, demonstrating that there were no major changes in susceptibility to penicillin from 1997-1998 (77.1% susceptible, 18.7% intermediate, 4.2% resistant). All S. Pneumoniae isolates from 1999-2000 were susceptible to levofloxacin and vancomycin and >90% were susceptible to the B-lactams (amoxicillin-clavulanate, ceftriaxone, and cefuroxime) and macrolides (axithyromycin and clarithromycin), showing that susceptibility to these agents also remained unchanged since 1997-1998. The most notable increase in resistance between the two studies was demonstrated by trimethoprim-sulfamethoxazole, which increased from 23.4% to 38.6%. Penicillin resistance correlated with resistance to B-lactams, macrolides, and trimethoprim-sulfamethoxazole in both studies. In H. influenzae, the prevalence of B-lactamase-producing isolates remained unchanged (10.6% in 1999-2000; 11.0% in 1997-1998). All H. influenzae isolates were susceptible to levofloxacine, ceftriaxone, cefuroxime, and azithromycin, and showed no change between the two studies. Trimethoprim-sulfamethoxazole resistance was present in 40.1% of isolates in 1999-2000, and in 45.2% in 1997-1998. In M. catarrhalis, the prevalence of B-lactamase-producing isolates was unchanged (97.9% in 1999-2000;98.0% in 1997-1998). The most active agents against M. catarrhalis were azithromycin (MIC(90),< or = 0.03 microg/ml) and levofloxacin (MIC(90),< or = 0.03 microg/ml). Overall, these results suggest that, in Brazil, between 1999-2000 and 1997-1998, there have been no significant changes in the susceptibility of respiratory pathogens to any of the commonly tested and prescribed agents with the exception of trimethoprim-sulfamethoxazole for S. Pneumoniae.

ABSTRACT Longitudinal surveillance of Enterobacteriaceae for antimicrobial susceptibility is important because species of this family are among the most significant and prevalent human pathogens. To estimate rates of in vitro antimicrobial susceptibility among hospitalized patients in the United States, data from The Surveillance Network were studied for 14 agents tested against 10 species of Enterobacteriaceae ( n = 384,279) isolated from intensive-care-unit (ICU) patients and non-ICU inpatients from 1998 to 2001. Cumulative susceptibility (percent) data for all species of Enterobacteriaceae isolated from ICU patients and non-ICU inpatients, respectively, were ranked as follows: ampicillin-sulbactam (45.5 and 57.2) ≪ ticarcillin-clavulanate (74.8 and 83.5) < trimethoprim-sulfamethoxazole (87.0 and 84.5) ≅ cefotaxime (82.9 and 92.6) = ceftazidime (82.3 and 91.0) = ceftriaxone (86.5 and 93.9) = piperacillin-tazobactam (83.5 and 90.5) < levofloxacin (89.3 and 90.6) = ciprofloxacin (91.0 and 91.7) < gentamicin (91.8 and 94.3) < cefepime (95.0 and 97.9) < amikacin (98.5 and 99.2) < imipenem (100 and 100) = meropenem (100 and 100). Of those agents studied only susceptibilities to ciprofloxacin (94 to 89%) and levofloxacin (93 to 89%) decreased in a stepwise manner from 1998 to 2001. Decreased fluoroquinolone susceptibility was most pronounced for Escherichia coli , Proteus mirabilis , and Enterobacter cloacae . For all species of Enterobacteriaceae , trimethoprim-sulfamethoxazole resistance was more commonly observed in isolates with a single-drug resistance phenotype while gentamicin and fluoroquinolone resistances were more common in isolates resistant to at least one additional class of antimicrobial agent. Ongoing surveillance of Enterobacteriaceae will be particularly important to monitor changes in fluoroquinolone susceptibility, as well as changes in the prevalence of isolates resistant to multiple classes of antimicrobial agents.