C-2 derivatized 8-sulfonamidoquinolines as antibacterial compounds.

A series of C-2 derivatized 8-sulfonamidoquinolines were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc (50 µM ZnSO4). The vast majority of compounds tested were demonstrated to be significantly more active against S. uberis when in the presence of supplementary zinc (MICs as low as 0.125 µg/mL were observed in the presence of 50 µM ZnSO4). Compounds 5, 34-36, 39, 58, 79, 82, 94 and 95 were shown to display the greatest antibacterial activity against S. aureus (MIC ≤ 8 µg/mL; both in the presence and absence of supplementary zinc), while compounds 56, 58 and 66 were demonstrated to also exhibit activity against E. coli (MIC ≤ 16 µg/mL; under all conditions). Compounds 56, 58 and 66 were subsequently confirmed to be bactericidal against all three mastitis pathogens studied, with MBCs (≥3log10 CFU/mL reduction) of ≤ 32 µg/mL (in both the presence and absence of 50 µM ZnSO4). To validate the sanitizing activity of compounds 56, 58 and 66, a quantitative suspension disinfection (sanitizer) test was performed. Sanitizing activity (>5log10 CFU/mL reduction in 5 min) was observed against both S. uberis and E. coli at compound concentrations as low as 1 mg/mL (compounds 56, 58 and 66), and against S. aureus at 1 mg/mL (compound 58); thereby validating the potential of compounds 56, 58 and 66 to function as topical sanitizers designed explicitly for use in non-human applications.

Substituted sulfonamide bioisosteres of 8-hydroxyquinoline as zinc-dependent antibacterial compounds.

A series of substituted sulfonamide bioisosteres of 8-hydroxyquinoline were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc. Compounds 9a-e, 10a-c, 11a-e, 12 and 13 were demonstrated to have MICs of 0.0625 µg/mL against S. uberis in the presence of 50 µM ZnSO4. Against S. aureus compounds 9g (MIC 4 µg/mL) and 11d (MIC 8 µg/mL) showed the greatest activity, whereas all compounds were found to be inactive against E. coli (MIC > 256 µg/mL); again in the presence of 50 µM ZnSO4. All compounds were demonstrated to be significantly less active in the absence of supplementary zinc. Compound 9g was subsequently confirmed to be bactericidal, with an MBC (≥3log10 cfu/mL reduction) of 0.125 µg/mL against S. uberis in the presence of 50 µM ZnSO4. To validate the sanitising activity of compound 9g in the presence of supplementary zinc, a quantitative suspension disinfection (sanitizer) test was performed. In this preliminary test, sanitizing activity (>5log10 reduction of CFU/mL in 5 min) was observed against S. uberis for compound 9g at concentrations as low as 1 mg/mL, validating the potential of this compound to function as a topical sanitizer against the major environmental mastitis-causing microorganism S. uberis.

The 2016 Garrod Lecture: The role of the healthcare epidemiologist in antimicrobial chemotherapy-a view from the USA.

Antimicrobial chemotherapy now spans 80 years and four generations. The healthcare epidemiologist has an important role to play in this field. Efforts focus in three areas: (i) minimizing the transmission of antimicrobial-resistant bacteria in healthcare settings (infection control); (ii) optimizing use of currently available antibacterial drugs (antibiotic stewardship); and (iii) recognizing and responding to opportunities for new drug development. For each area, the epidemiologist provides data that address four practical questions-'What is the problem?', 'What should be done?', 'Is it being done?' and 'Is it working?'. A team approach is crucial to acting on the epidemiological data. Examples are presented to illustrate different roles of the epidemiologist, and tools and measures that have been developed to address some problems of current importance. Monitoring of quality, integrity and security of data remains a major focus. The epidemiologist will continue to have a key role in antimicrobial chemotherapy.

Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage in residents of Veterans Affairs long-term care facilities: role of antimicrobial exposure and MRSA acquisition.

OBJECTIVE: To identify risk factors associated with methicillin-resistant Staphylococcus aureus (MRSA) acquisition in long-term care facility (LTCF) residents. DESIGN: Multicenter, prospective cohort followed over 6 months. SETTING: Three Veterans Affairs (VA) LTCFs. PARTICIPANTS: All current and new residents except those with short stay (<2 weeks). METHODS: MRSA carriage was assessed by serial nares cultures and classified into 3 groups: persistent (all cultures positive), intermittent (at least 1 but not all cultures positive), and noncarrier (no cultures positive). MRSA acquisition was defined by an initial negative culture followed by more than 2 positive cultures with no subsequent negative cultures. Epidemiologic data were collected to identify risk factors, and MRSA isolates were typed by pulsed-field gel electrophoresis (PFGE). RESULTS: Among 412 residents at 3 LTCFs, overall MRSA prevalence was 58%, with similar distributions of carriage at all 3 facilities: 20% persistent, 39% intermittent, 41% noncarriers. Of 254 residents with an initial negative swab, 25 (10%) acquired MRSA over the 6 months; rates were similar at all 3 LTCFs, with no clusters evident. Multivariable analysis demonstrated that receipt of systemic antimicrobials during the study was the only significant risk factor for MRSA acquisition (odds ratio, 7.8 [95% confidence interval, 2.1-28.6]; P = .002). MRSA strains from acquisitions were related by PFGE to those from a roommate in 9/25 (36%) cases; 6 of these 9 roommate sources were persistent carriers. CONCLUSIONS: MRSA colonization prevalence was high at 3 separate VA LTCFs. MRSA acquisition was strongly associated with antimicrobial exposure. Roommate sources were often persistent carriers, but transmission from roommates accounted for only approximately one-third of MRSA acquisitions.

Antimicrobial stewardship--the state of the art in 2011: focus on outcome and methods.

Antimicrobial stewardship programs attempt to optimize prescribing of these drugs to benefit both current and future patients. Recent regulatory and other incentives have led to widespread adoption of such programs. Measurements of the success of these programs have focused primarily on process measures. However, evaluation of outcome measures will be needed to ensure sustainability of these efforts. Outcome efforts to date provide some evidence for improved care of individual patients, some evidence for minimizing emergence of resistance, and ample evidence for cost reduction. Attention to evaluation methods must be increased to provide convincing evidence for the continuation of such programs.

Hospitalization earlier than 1 year prior to admission as an additional risk factor for methicillin-resistant Staphylococcus aureus colonization.

Our case-control study sought to identify risk factors for colonization with methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission among patients with no known healthcare-related risk factors. We found that patients whose most recent hospitalization occurred greater than 1 year before their current hospital admission were more likely to have MRSA colonization. In addition, both the time that elapsed since the most recent hospitalization and the duration of that hospitalization affected risk.

Comparison of typing results obtained for methicillin-resistant Staphylococcus aureus isolates with the DiversiLab system and pulsed-field gel electrophoresis.

We compared the results of typing methicillin-resistant Staphylococcus aureus (MRSA) isolates using the DiversiLab system (DL) to the results obtained using pulsed-field gel electrophoresis (PFGE). One hundred five MRSA isolates of PFGE types USA100 to USA1100 and the Brazilian clone, from the Centers for Disease Control and Prevention (CDC) and Project ICARE strain collections, were typed using DL. In addition, four unique sets of MRSA isolates from purported MRSA outbreaks that had been previously typed by DL, each consisting of six isolates (where five isolates were classified as indistinguishable by DL and one was an unrelated DL type) were typed by PFGE. DL separated the 105 MRSA isolates of known USA types into 11 clusters and six unique banding patterns. DL grouped most of the USA100, USA200, and USA1100 isolates into unique clusters. Multilocus sequence type 8 isolates (i.e., USA300 and USA500) often clustered together at >95% similarity in DL dendrograms. Nevertheless, USA300 and USA500 DL patterns could be distinguished using the pattern overlay function of the DL software. Among the hospital outbreak clusters, PFGE and DL identified the same "unrelated" organism in three of four sets. However, PFGE showed more pattern diversity than did DL, suggesting that two of the sets were less likely to represent true outbreaks. In summary, DL is useful for screening MRSA isolates to rule out potential outbreaks of MRSA in hospitals, but PFGE provides better discrimination of potential outbreak strains and is more useful for confirming strain relatedness and specific USA types.

Characterisation of a Staphylococcus aureus strain with progressive loss of susceptibility to vancomycin and daptomycin during therapy.

Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2 microg/mL to 8 microg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy.

Identification of plasmid-mediated AmpC beta-lactamases in Escherichia coli, Klebsiella spp., and proteus species can potentially improve reporting of cephalosporin susceptibility testing results.

The goal of this study was to determine if the interpretations of extended-spectrum and advanced-spectrum cephalosporins (ESCs and ASCs, respectively) for isolates of Enterobacteriaceae would be impacted by the results of aminophenylboronic acid (APBA) testing. Fifty-three isolates of Escherichia coli, 21 Klebsiella species, and 6 Proteus species that were resistant to at least one ESC were tested by disk diffusion with ceftazidime and cefotetan disks with and without APBA. Ceftazidime disks with and without clavulanic acid (CLAV) were also tested to confirm extended-spectrum beta-lactamase (ESBL) carriage. Twenty-nine (36.3%) isolates were only APBA test positive, 27 were only CLAV test positive, 2 were positive with both substrates, and 22 were negative with both substrates. Thirteen (41.9%) of the 31 APBA-test-positive isolates (all E. coli) tested susceptible to cefotaxime, ceftriaxone, or ceftazidime. Since clinical data suggest that AmpC-producing isolates should be reported as resistant to all ESCs, APBA testing can be helpful in identifying such organisms. Screening for AmpC-producing organisms using nonsusceptibility to cefoxitin and amoxicillin-clavulanate was less specific than APBA testing; it identified ESBL as well as AmpC-producing organisms. Only 18 of 31 APBA-positive isolates were positive by PCR for an AmpC beta-lactamase gene. Thus, testing with APBA could improve the accuracy of reporting ESCs, especially for E. coli. However, results of APBA and CLAV testing did not correlate well for isolates containing both AmpC beta-lactamases and ESBLs. Thus, additional data are needed before formal recommendations can be made on changing the reporting of ASC test results.

Cytomegalovirus seroprevalence and childhood sources of infection: A population-based study among pre-adolescents in the United States.

BACKGROUND: Among pre-adolescents, the importance of different sources of cytomegalovirus (CMV) infection is unclear. OBJECTIVE: To assess the importance of several CMV sources among pre-adolescent children. STUDY DESIGN: We used data from a United States population-based sample conducted from 1988 to 1994: 4-10-year-old participants (n=3386) of the Third National Health and Nutrition Examination Survey. We tested available sera for CMV-specific-IgG and assessed CMV prevalence differences by surrogates for exposure to childhood CMV sources (maternal CMV serostatus, breast-feeding, older sibling CMV serostatus, and child care center attendance). RESULTS: CMV infection was more prevalent (70%) among Mexican American children with foreign-born householders than among children with native-born householders (31% non-Hispanic White, 39% non-Hispanic Black, and 37% Mexican American children). Child's serostatus was associated with their mother's (prevalence difference range (PDR)=33-40%) and older sibling's serostatus (PDR=39-50%). Breast-feeding was associated with CMV in some racial/ethnic and householder groups (PDR=-5.1% to 22.7%). There was little difference in CMV seroprevalence by child care center attendance (PDR=-6.5% to -0.4%). CONCLUSIONS: This study expands understanding of CMV by identifying the importance of householder nativity and demonstrating the importance of family transmission among the general population of pre-adolescents.

Health care-associated pneumonia (HCAP): a critical appraisal to improve identification, management, and outcomes--proceedings of the HCAP Summit.

Increasingly, patients are receiving treatment at facilities other than hospitals, including long-term-health care facilities, assisted-living environments, rehabilitation facilities, and dialysis centers. As with hospital environments, nonhospital settings present their own unique risks of pneumonia. Traditionally, pneumonia in these facilities has been categorized as community-acquired pneumonia (CAP). However, the new designation for pneumonias acquired in these settings is health care-associated pneumonia (HCAP), which covers pneumonias acquired in health care environments outside of the traditional hospital setting and excludes hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and CAP. Although HCAP is currently treated with the same protocols as CAP, recent evidence indicates that HCAP differs from CAP with respect to pathogens and prognosis and, in fact, more closely resembles HAP and VAP. The HCAP Summit convened national infectious disease opinion leaders for the purpose of analyzing current literature, clinical trial data, diagnostic considerations, therapeutic options, and treatment guidelines related to HCAP. After an in-depth analysis of these areas, the infectious disease investigators participating in the summit were surveyed with regard to 10 clinical practice statements. The results were then compared with results of the same survey as completed by 744 Infectious Diseases Society of America members. The similarities and differences between those survey results are the basis of this publication.

Antimicrobial resistance: international control strategies, with a focus on limited-resource settings.

Microorganisms resistant to multiple anti-infective agents have increased worldwide. These organisms threaten both optimal care of patients with infection as well as the viability of current healthcare systems. In addition, antimicrobials are valuable resources that enhance both prevention and treatment of infections. As resistance diminishes this resource, it is a societal goal to minimise resistance and therefore to reduce forces that produce resistance. This review considers strategies for minimising resistance that are needed at several different levels of responsibility, ranging from the patient care provider to international agencies. It then describes responses that might be appropriate according to the resources available for control, focusing on limited-resource settings. Antimicrobial resistance represents an international concern. Response to this problem demands concerted efforts from multiple sectors both in developed and developing countries, as well as the strengthening of multinational/international partnerships and regulations. Both medical and public health agencies should be in the forefront of these efforts.

Influence of sexual activity on cytomegalovirus seroprevalence in the United States, 1988-1994.

BACKGROUND: Sexual and nonsexual transmission of cytomegalovirus (CMV) occurs, but the frequency of sexual transmission in the general population of the United States is unknown. METHODS: Using data from 15- to 44-year-old (n = 7883) participants of the Third National Health and Nutrition Examination Survey (1988-1994), we examined the association between CMV seroprevalence and sexual activity markers. Using logistic regression, we calculated standardized prevalence differences (PDs)-the weighted average CMV prevalence among higher sexual risk groups minus CMV prevalence among the lowest sexual risk group-for each of several sexual activity markers (ever had sex, number of sex partners [lifetime and past year], age at first intercourse, potential years of sexual activity, ever use oral contraceptives, herpes simplex virus type 2 antibody, and a calculated composite marker). RESULTS: Even after controlling for covariates, we found associations between CMV seroprevalence and sexual activity among non-Hispanic black [all PDs for sexual activity markers were positive and composite PD = 8.5%, 95% confidence interval (CI) = 4.0%-13.1%] and non-Hispanic white women (15 of 18 PDs for sexual activity markers were positive and composite PD = 10.8%, 95% CI = 3.1%-18.5%). We found a borderline significant association among Mexican American women (13 of 18 PDs for sexual activity markers were positive and composite PD = 3.5%, 95% CI = -0.7% to 7.6%). We found little or no association within each racial/ethnic group of men. CONCLUSIONS: Sexual activity measurably influences CMV seroprevalence among women of childbearing age, indicating that congenital CMV prevention messages should include strategies to reduce sexual transmission of CMV among pregnant women.

High rate of mobilization for blaCTX-Ms.

We constructed a phylogenetic analysis of class A beta-lactamases and found that the blaCTX-Ms have been mobilized to plasmids approximately 10 times more frequently than other class A beta-lactamases. We also found that the blaCTX-Ms are descended from a common ancestor that was incorporated in ancient times into the chromosome of the ancestor of Kluyvera species through horizontal transfer. Considerable sequence divergence has occurred among the descendents of that ancestral gene sequence since that gene was inserted. That divergence has mainly occurred in the presence of purifying selection, which indicates a slow rate of evolution for blaCTX-Ms in the pre-antimicrobial drug era.

Importance of bacterial burden among methicillin-resistant Staphylococcus aureus carriers in a long-term care facility.

OBJECTIVE: To evaluate the prevalence and transmission of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization, as well as risk factors associated with MRSA carriage, among residents of a long-term care facility (LTCF). DESIGN: Prospective, longitudinal cohort study. SETTING: A 100-bed Veterans Administration LTCF. PARTICIPANTS: All current and newly admitted residents of the LTCF during an 8-week study period. METHODS: Nasal swab samples were obtained weekly and cultured on MRSA-selective media, and the cultures were graded for growth on a semiquantitative scale from 0 (no growth) to 6 (heavy growth). Epidemiologic data for the periods before and during the study were collected to assess risk factors for MRSA carriage. RESULTS: Of 83 LTCF residents, 49 (59%) had 1 or more nasal swab cultures that were positive for MRSA; 34 (41%) were consistently culture-negative (designated "noncarriers"). Of the 49 culture-positive residents, 30 (36% of the total of 83 residents) had all cultures positive for MRSA (designated "persistent carriers"), and 19 (23% of the 83 residents) had at least 1 culture, but not all cultures, positive for MRSA (designated "intermittent carriers"). Multivariate analysis showed that participants with at least 1 nasal swab culture positive for MRSA were likely to have had previous hospitalization (odds ratio, 3.9) or wounds (odds ratio, 8.2). Persistent carriers and intermittent carriers did not differ in epidemiologic characteristics but did differ in mean MRSA growth score (3.7 vs 0.7; P<.001). CONCLUSIONS: Epidemiologic characteristics differed between noncarriers and subjects with at least 1 nasal swab culture positive for MRSA. However, in this LTCF population, only the degree of bacterial colonization (as reflected by mean MRSA growth score) distinguished persistent carriers from intermittent carriers. Understanding the burden of colonization may be important when determining future surveillance and control strategies.

Antimicrobial resistance prevention initiative--an update: proceedings of an expert panel on resistance.

Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. It is a worldwide problem that spans the range of human pathogens, including bacteria, fungi, and viruses. This update from the Antimicrobial Resistance Prevention Initiative (ARPI) provides a review of some important trends in antibiotic, antifungal, and antiviral resistance. Areas of focus include multidrug-resistant bacteria in the hospital setting; the growing problem of community-acquired methicillin-resistant Staphylococcus aureus; triazole and polyene resistance in nosocomial infections caused by non-Candida albicans or Aspergillus species, and the utility of in vitro susceptibility testing for these fungal infections; antiviral resistance in alpha- or beta-herpesviruses causing genital herpes or cytomegalovirus infection in immunocompromised hosts; and concerns about a possible pandemic involving avian influenza A and the importance of minimizing emergence of resistant strains of this highly pathogenic virus. The challenges in each area are different, but the general keys to addressing the growing problem of antimicrobial resistance continue to be responsible antimicrobial stewardship and the development of newer antimicrobial agents.

Accuracy of six antimicrobial susceptibility methods for testing linezolid against staphylococci and enterococci.

A challenge panel of enterococci (n = 50) and staphylococci (n = 50), including 17 and 15 isolates that were nonsusceptible to linezolid, respectively, were tested with the Clinical and Laboratory Standards Institute broth microdilution and disk diffusion reference methods. In addition, all 100 isolates were tested in parallel by Etest (AB Biodisk, Solna, Sweden), MicroScan WalkAway (Dade, West Sacramento, CA), BD Phoenix (BD Diagnostic Systems, Sparks, MD), VITEK (bioMérieux, Durham, NC), and VITEK 2 (bioMérieux) by using the manufacturers' protocols. Compared to the results of the broth microdilution method for detecting linezolid-nonsusceptible staphylococci and enterococci, MicroScan results showed the highest category agreement (96.0%). The overall categorical agreement levels for VITEK 2, Etest, Phoenix, disk diffusion, and VITEK were 93.0%, 90.0%, 89.6%, 88.0%, and 85.9%, respectively. The essential agreement levels (results within +/-1 doubling dilution of the MIC determined by the reference method) for MicroScan, Phoenix, VITEK 2, Etest, and VITEK were 99.0%, 95.8%, 92.0%, 92.0%, and 85.9%, respectively. The very major error rates for staphylococci were the highest for VITEK (35.7%), Etest (40.0%), and disk diffusion (53.3%), although the total number of resistant isolates tested was small. The very major error rate for enterococci with VITEK was 20.0%. Three systems (MicroScan, VITEK, and VITEK 2) provided no interpretations of nonsusceptible results for staphylococci. These data, from a challenge panel of isolates, illustrate that the recent emergence of linezolid-nonsusceptible staphylococci and enterococci is providing a challenge for many susceptibility testing systems.

Antimicrobial resistance prevention initiative--an update: proceedings of an expert panel on resistance.

Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. It is a worldwide problem that spans the range of human pathogens, including bacteria, fungi, and viruses. This update from the Antimicrobial Resistance Prevention Initiative (ARPI) provides a review of some important trends in antibiotic, antifungal, and antiviral resistance. Areas of focus include multidrug-resistant bacteria in the hospital setting; the growing problem of community-acquired methicillin-resistant Staphylococcus aureus; triazole and polyene resistance in nosocomial infections caused by non-Candida albicans or Aspergillus species, and the utility of in vitro susceptibility testing for these fungal infections; antiviral resistance in alpha- or beta-herpesviruses causing genital herpes or cytomegalovirus infection in immunocompromised hosts; and concerns about a possible pandemic involving avian influenza A and the importance of minimizing emergence of resistant strains of this highly pathogenic virus. The challenges in each area are different, but the general keys to addressing the growing problem of antimicrobial resistance continue to be responsible antimicrobial stewardship and the development of newer antimicrobial agents.