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Objectives: Point prevalence estimates of extended-spectrum cephalosporin-resistant Escherichia coli (ESC-R-Ec) are important surveillance measures but may not uncover the ESC-R-Ec dynamics within pig farms. A longitudinal study was therefore performed by sampling individual pigs, pig farmers and the environment., Methods: On average, 30 (range 10-46) piglets of 31 Swiss farms were sampled during the suckling, weaning and fattening stages (n= 2437 samples). In addition, stool from pig farmers and environmental samples were obtained and metadata collected by questionnaires. ESC-R-Ec was identified by routine culture, and clonal relationships and resistance genes were derived from whole genome sequencing data., Results: Working on pig farms was not associated with an increased prevalence of ESC-R-Ec in humans. ESC-R-Ec prevalence significantly decreased from 6.2% to 3.9% and 1.8% for the suckling, weaned and fattening pigs, respectively (P < 0.001). Within the 57 ESC-R-positive suckling piglets, persisting carriage was detected in 25 animals at two consecutive time points and one animal at three consecutive time points. Clonal spread (n=7 farms, 22.6%) and horizontal gene transfer (n=1 farm, 3%) within pigs but not between humans and animals was detected. Liquid manure (n=10 samples, 16.7%) was identified as the major environmental reservoir of ESC-R-Ec in the pig farm environment., Conclusions: Pig farming practices like all-in-all-out systems, but not antimicrobial usage, were associated with reduced risk of ESC-R-Ec at the farm level. As carriage duration is normally short within the individual pigs, the risk of recolonisation and clonal spread of ESC-R-Ec might be reduced by applying appropriate decontamination strategies., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Study Objective: Third-generation cephalosporin-resistant (3GCR) Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis (EKP) are an increasingly common cause of community-onset urinary tract infections (UTIs) in the United States. The 3GCR antimicrobial resistance pattern in these Enterobacterales species is most commonly due to production of extended-spectrum β-lactamases. We sought to provide contemporary, emergency department (ED)-focused data on 3GCR-EKP UTI regional prevalence, presentation, antibiotic susceptibility, and empiric treatment patterns, and outcomes., Methods: We performed a retrospective cohort study of all adults admitted with a febrile UTI at 21 Kaiser Permanente Northern California EDs between January 2017 and June 2019. Inclusion criteria included fever; admitting diagnosis of UTI, pyelonephritis, or sepsis; and ED urine culture with greater than 100,000 colony-forming units/mL of an EKP species. 3GCR was defined as in vitro resistance to ceftriaxone, ceftazidime, or both. 3GCR-EKP cases were compared with non-3GCR-EKP controls for the following: demographics, comorbidities, presenting clinical features, urinary isolate antimicrobial susceptibility, treatment, and clinical outcomes. The primary outcome measure was the rate of discordant initial empiric antibiotic treatment (administered within 6 hours of ED arrival) when compared with antimicrobial susceptibility testing. Secondary outcomes included hospital length of stay and 90-day mortality, adjusted for comorbidities and severity of illness., Results: There were 4,107 patients (median age 73 years and 35% men) who met study inclusion criteria. Of these patients, 530 (12.9%) had a 3GCR-EKP urinary tract infection. The proportion of subjects possessing risk factors for a health care-associated or extended-spectrum β-lactamase infection was 92.8% of case patients and 86.1% of controls. When comparing 3GCR-EKP case and non-3GCR-EKP control isolates, ciprofloxacin susceptibility rates were 21% versus 88%, and piperacillin/tazobactam susceptibility rates were 89% versus 97%, respectively. Initial empiric antibiotic therapy was discordant with antimicrobial susceptibility testing results in 63% of case patients versus 7% of controls (odds ratio 21.0; 95% confidence interval 16.9 to 26.0). The hospital length of stay was longer for 3GCR-EKP case patients, with an adjusted mean difference of 29.7 hours (95% CI 19.0 to 40.4). Ninety-day mortality was 12% in case patients versus 8% in controls (adjusted odds ratio 1.56; 95% confidence interval 1.07 to 2.28)., Conclusion: In this large, 2017 to 2019 Northern California ED study, nearly 13% of febrile EKP UTIs requiring hospitalization were caused by 3GCR-EKP, and in these cases, initial empiric therapy was often discordant with antimicrobial susceptibility testing. 3GCR-EKP infections were associated with a longer hospital length of stay and higher 90-day mortality. Similar data from other regions and for outpatient UTIs are needed., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

The recent emergence of strains of Neisseria gonorrhoeae associated with treatment failures to ceftriaxone, the foundation of current treatment options, has raised concerns over a future of untreatable gonorrhea. Current global data on gonococcal strains suggest that several lineages, predominately characterized by mosaic penA alleles, are associated with elevated minimum inhibitory concentrations (MICs) to extended spectrum cephalosporins (ESCs). Here we report on whole genome sequences of 813 N. gonorrhoeae isolates collected through the Gonococcal Isolate Surveillance Project in the United States. Phylogenomic analysis revealed that one persisting lineage (Clade A, multi-locus sequence type [MLST] ST1901) with mosaic penA-34 alleles, contained the majority of isolates with elevated MICs to ESCs. We provide evidence that an ancestor to the globally circulating MLST ST1901 clones potentially emerged around the early to mid-20th century (1944, credibility intervals [CI]: 1935-1953), predating the introduction of cephalosporins, but coinciding with the use of penicillin. Such results indicate that drugs with novel mechanisms of action are needed as these strains continue to persist and disseminate globally.

Aims: Although a link between agricultural cephalosporin use and resistance in Salmonella has been demonstrated with the drug ceftiofur, the underlying mechanism of the correlation is unclear. This study investigated the impact of ceftiofur exposure in S. Saintpaul on ceftriaxone resistance, the gene expression and the conjugative transfer of the bla CTX-M-65 gene., Methods and Results: Prior ceftiofur exposure caused a twofold increase in MIC from 1024 to 2048 µg ml -1 towards ceftriaxone and increased the enzymatic activity of Bla CTX-M-65 2·2 folds from 3·46 to 7·67 nmol nitrocefin hydrolysed min -1 . A threefold upregulation in gene expression of the bla CTX-M-65 gene was also observed. Donors exposed to ceftiofur subsequently demonstrated a 2·5-fold decrease in transfer efficiency., Conclusions: Prior exposure of S. Saintpaul to ceftiofur led to increased phenotypic resistance towards ceftriaxone while its ability to spread the cephalosporin resistance through conjugation, conversely, was impaired., Significance and Impact of the Study: Findings from this study shed light on one possible mechanism in which agricultural cephalosporin exposure in Salmonella may subsequently impact clinical treatment. The finding that cephalosporin exposure in donors may hinder the subsequent spread of resistance instead of aiding it up was counter-intuitive., (© 2020 The Society for Applied Microbiology.)

Antimicrobial resistance is a public health concern. Understanding any role that urban seagulls may have as a reservoir of resistant bacteria could be important for reducing transmission. This study investigated fecal Escherichia coli isolates from seagulls (herring gulls and lesser black-backed gulls) to determine the prevalence of extended-spectrum cephalosporin-resistant (ESC-R) and fluoroquinolone-resistant E. coli among gull species from two cities (Taunton and Birmingham) in the United Kingdom (UK). We characterized the genetic background and carriage of plasmid-mediated resistance genes in extended-spectrum β-lactamase (ESBL)-producing E. coli obtained from these birds. Sixty ESC-R E. coli isolates were obtained from 39 seagulls (39/78, 50%), of which 28 (28/60, 46.7%) were positive for plasmid-mediated CTX-M and/or AmpC β-lactamase resistance genes. Among these, bla CTX-M-15 , bla CTX-M-14 , and bla CMY-2 predominated. Three isolates belonging to the B2-ST131 clone were detected, of which two harbored bla CTX-M-15 (typed to C2/H30Rx) and one harbored bla CTX-M-27 and was typed to C1/H30-R (recently described as the C1-M27 sublineage). The plasmid-mediated quinolone resistance (PMQR) gene carriage prevalence (11.7%) consisted of aac(6')-Ib-cr and qnrB genes. No carbapenem or colistin resistance genes were detected. Urban seagulls in the UK are colonized and can spread major antimicrobial-resistant E. coli isolates harboring ESBL and PMQR determinants, including clinically important strains such as the pandemic clone B2-ST131 and the C1-M27 subclade. This is the first report of ST131-C1-M27 subclade in wildlife in the UK and in seagulls worldwide.

Neisseria gonorrhoeae is a principal pathogen for sexually transmitted infections, especially for male urethritis. Currently, the prevalence of multidrug resistance is increasing. Carbapenems are broad-spectrum antimicrobials that are widely used in the clinical setting, especially for multidrug-resistant Gram-negative bacteria. However, susceptibility to carbapenems has not been well evaluated for cephalosporin-resistant N. gonorrhoeae isolates. In this study, we determined the susceptibility to a series of carbapenems (meropenem, imipenem, doripenem, and biapenem) and faropenem against cephalosporin-resistant (resistant to cefixime, but susceptible to ceftriaxone) and cephalosporin-susceptible N. gonorrhoeae clinical isolates. The gene mutations associated with β-lactam resistance were evaluated. All cephalosporin-resistant N. gonorrhoeae isolates possessed mosaic mutation alleles in penA (NG-STAR penA-10.001, 27.001, or 108.001). They exhibited a low minimum inhibitory concentration (MIC) (≤0.125 mg/L) for meropenem and markedly high MICs (0.5-2 mg/L) for other carbapenems and faropenem. The strongest association was observed between the mosaic alleles in penA and decreased susceptibility to carbapenems and faropenem compared with mutations in mtrR, porB, and ponA. These results suggest that meropenem may serve as an alternative therapeutic agent for cephalosporin-resistant N. gonorrhoeae with a mosaic allele in penA, whereas other carbapenems and faropenem may be ineffective.

Background: Bacterial resistance to first line antibiotics used to treat community-onset urinary tract infections (UTIs) continues to emerge. We sought to determine the association between extended-spectrum cephalosporin resistance (ESC-R) and recurrence among Enterobacteriaceae (EB) UTIs., Methods: A retrospective cohort study was performed. All patients presenting to the Emergency Departments (EDs) or outpatient practices in a large health system with EB UTIs between 2010 and 2013 were included. Exposed patients had ESC-R EB UTIs. Unexposed patients had ESC-susceptible EB UTIs and were matched to exposed patients 1:1 on study year. Multivariable Cox proportional hazards regression analyses were performed to evaluate the association between ESC-R EB UTI and time to recurrent UTI within 12 months., Results: A total of 302 patients with an index community-onset EB UTI were included, with 151 exposed and 151 unexposed. Overall, 163 (54%) patients experienced a recurrent UTI with a median time to recurrence of 69 days (interquartile range 25-183). On multivariable analyses, ESC-resistance was associated with an increased hazard of recurrent UTI (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.01-1.91, P = 0.04). Other variables that were independently associated with recurrence included a history of UTI prior to the index UTI and presence of a urinary catheter at the time of the index UTI. Secondarily, we found that when the treatment for the index UTI was adjusted for, there was no longer a significant association between ESC-R status and time to recurrent UTI (aHR 1.26, 95% CI 0.91-1.76, P = 0.17)., Conclusions: Community-onset UTI due to EB demonstrating ESC-resistance is associated with a significantly increased hazard of recurrent UTI within 12 months compared to ESC-susceptible EB, even after adjusting for baseline factors that predispose patients to UTI recurrence. This association appears to be driven primarily by delayed or inappropriate treatment for the index ESC-R EB UTI.

Background: The widespread antimicrobial resistance of Neisseria gonorrhoeae is a serious problem for the treatment and control of gonorrhoea. Many of the previously effective therapeutic agents are no longer viable. Because N. gonorrhoeae infections are not reportable in Germany, only limited data on disease epidemiology and antimicrobial susceptibility patterns are available. The Gonococcal Resistance Network (GORENET) is a surveillance project to monitor trends in the antimicrobial susceptibility of N. gonorrhoeae in Germany in order to guide treatment algorithms and target future prevention strategies., Methods: Between April 2014 and December 2015, data on patient-related information were collected from laboratories nationwide, and susceptibility testing was performed on 537 N. gonorrhoeae isolates forwarded from the network laboratories to the Conciliar Laboratory for gonococci. Susceptibility results for cefixime, ceftriaxone, azithromycin, ciprofloxacin and penicillin were defined according to EUCAST 4.0 standards. Percentages, medians and interquartile ranges (IQR) were calculated., Results: Altogether, 90% of isolates were from men. The median age was 32 (IQR 25-44) years for men and 25 (IQR 22-40) years for women (p-value < 0.001). The most frequently tested materials among men were urethral (96.1%) and rectal swabs (1.7%), and among women, it was mainly endocervical and vaginal swabs (84.3%). None of the isolates were resistant to ceftriaxone. Furthermore, 1.9% (in 2014) and 1.4% (in 2015) of the isolates were resistant to cefixime, 11.9% and 9.8% showed resistance against azithromycin, 72.0% and 58.3% were resistant to ciprofloxacin, and 29.1% and 18.8% were resistant to penicillin., Conclusions: Resistance to ceftriaxone was not detected, and the percentage of isolates with resistance to cefixime was low, whereas azithromycin resistance showed high levels during the observation period. The rates of ciprofloxacin resistance and penicillin resistance were very high across Germany. Continued surveillance of antimicrobial drug susceptibilities for N. gonorrhoeae remains highly important to ensure efficient disease management.

Neisseria gonorrhoeae isolates with decreased susceptibility to extended-spectrum cephalosporins (ESCs) are increasing. We developed an assay to predict N. gonorrhoeae susceptibility to ESCs by targeting penA mosaic XXXIV, an allele prevalent among U.S. isolates with elevated ESC MICs. The assay was 97% sensitive and 100% specific for predicting at least one ESC MIC above the CDC alert value among clinical isolates, and it could be multiplexed with a previously validated gyrA PCR to predict ciprofloxacin susceptibility., (Copyright © 2017 American Society for Microbiology.)

In the US, nontyphoidal Salmonellae are a common foodborne zoonotic pathogen causing gastroenteritis. Invasive Salmonella infections caused by extended-spectrum cephalosporin resistant (ESCR) phenotypes are more likely to result in treatment failure and adverse health outcomes, especially in severe pediatric Salmonella infections where the extended-spectrum β-lactams are the therapy of choice. To examine the genetic and epidemiologic characteristics of ESCR Salmonellae which may enter the food chain, we characterized 44 ceftiofur-resistant Salmonella isolates from the National Animal Health Monitoring System (NAHMS) 2011 beef cattle feedlot health and management study. As part of the NAHMS Feedlot 2011 study, 5050 individual fecal samples from 68 large (1000+ head capacity) feedlots were cultured for Salmonella spp. The resulting 460 positive samples yielded 571 Salmonella isolates with 44 (8%) expressing an AmpC β-lactamase phenotype. These phenotypic bla CMY-2 Salmonella isolates represented 8 serotypes, most commonly S. Newport (n=14, 32%), S. Typhimurium (n=13, 30%), and S. Reading (n=5, 11%), followed by S. Dublin, S. Infantis, S. Montevideo, S. Rough O:i;v:1;7, and S. Uganda. Carriage of the bla CMY-2 gene was confirmed for all isolates expressing an AmpC β-lactamase phenotype by PCR. Additionally, all 44 isolates were shown to carry the bla CMY-2 gene on a large IncA/C plasmid, a gene/plasmid combination which has been previously reported in multiple species. Other plasmids, including IncN, FIC, and FIIA, were also detected in some isolates. Cattle fed chlortetracycline were less likely to be positive for a bla CMY-2 Salmonella isolate in their enteric flora compared to those not receiving chlortetracycline during the feeding period. Carriage of bla CMY-2 was more prevalent in Salmonella isolates originating from lighter weight cattle, cattle fed tylosin and dairy breeds. Our characterization of the NAHMS Feedlot 2011 study Salmonella isolates with ESCR phenotype shows that while other cephalosporin resistance mechanisms have been reported in US cattle, specific serotypes harboring bla CMY-2 on IncA/C plasmids may be the dominant resistance genotype., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Surveillance of Neisseria gonorrhoeae antimicrobial susceptibility in Europe is performed through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), which additionally provides data to inform the European gonorrhoea treatment guideline; currently recommending ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. We present antimicrobial susceptibility data from 24 European countries in 2015, linked to epidemiological data of patients, and compare the results to Euro-GASP data from previous years., Methods: Antimicrobial susceptibility testing by MIC gradient strips or agar dilution methodology was performed on 2134 N. gonorrhoeae isolates and interpreted using EUCAST breakpoints. Patient variables associated with resistance were established using logistic regression to estimate odds ratios (ORs)., Results: In 2015, 1.7% of isolates were cefixime resistant compared to 2.0% in 2014. Ceftriaxone resistance was detected in only one (0.05%) isolate in 2015, compared with five (0.2%) in 2014. Azithromycin resistance was detected in 7.1% of isolates in 2015 (7.9% in 2014), and five (0.2%) isolates displayed high-level azithromycin resistance (MIC ≥ 256 mg/L) compared with one (0.05%) in 2014. Ciprofloxacin resistance remained high (49.4%, vs. 50.7% in 2014). Cefixime resistance significantly increased among heterosexual males (4.1% vs. 1.7% in 2014), which was mainly attributable to data from two countries with high cefixime resistance (~11%), however rates among men-who-have-sex-with-men (MSM) and females continued to decline to 0.5% and 1%, respectively. Azithromycin resistance in MSM and heterosexual males was higher (both 8.1%) than in females (4.9% vs. 2.2% in 2014). The association between azithromycin resistance and previous gonorrhoea infection, observed in 2014, continued in 2015 (OR 2.1, CI 1.2-3.5, p < 0.01)., Conclusions: The 2015 Euro-GASP sentinel system revealed high, but stable azithromycin resistance and low overall resistance to ceftriaxone and cefixime. The low cephalosporin resistance may be attributable to the effectiveness of the currently recommended first-line dual antimicrobial therapy; however the high azithromycin resistance threatens the effectiveness of this therapeutic regimen. Whether the global use of azithromycin in mono- or dual antimicrobial therapy of gonorrhoea is contributing to the global increases in azithromycin resistance remains to be elucidated. The increasing cefixime resistance in heterosexual males also needs close monitoring.

Background: The emergence of Neisseria gonorrhoeae strains with decreased susceptibility to cephalosporins represents a major concern globally. The aim of this study was to examine the phenotypic and molecular characteristics of N. gonorrhoeae isolates with decreased susceptibility to ceftriaxone and cefixime in Argentina., Methods: A total of 1987 isolates were collected during 2009 and 2013. The susceptibility to penicillin G, tetracycline, ciprofloxacin, cefixime, ceftriaxone, and azithromycin was determined using the agar dilution method. The major extended-spectrum cephalosporin resistance determinants (penA, mtrR, and porB1b) were sequenced in 42 N. gonorrhoeae isolates that showed decreased susceptibility to ceftriaxone (minimum inhibitory concentration [MIC], 0.06-0.125 mg/L) and cefixime (MIC, 0.125-0.25 mg/L). Genotyping by N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed., Results: Between 2009 and 2013, there was a shift in the modal MICs for ceftriaxone. Among the 42 isolates exhibiting decreased susceptibility to ceftriaxone and cefixime, 95.2% were resistant to penicillin G, 95.2% to tetracycline, 97.6% to ciprofloxacin, and 33.3% to azithromycin. Thirty-five (83.3%) of the 42 isolates had a mosaic penA allele XXXIV, which has been previously associated with resistance to ceftriaxone and cefixime as well as treatment failures. The isolates that contained the mosaic penicillin-binding protein 2 (PBP2) XXXIV were associated with NG-MAST ST1407 or closely related genotypes., Conclusions: In Argentina, N. gonorrhoeae isolates with decreased susceptibility to cefixime and ceftriaxone have now emerged, mostly due to the introduction of the internationally spread multidrug-resistant NG-MAST ST1407.

The aim of this study was to identify the presence of group CTX-M-9 extended spectrum beta-lactamases (ESBL) in clinical Escherichia coli isolates from pediatric patients. A total of 404 non-repeated positive ESBL E. coli isolates were collected from documented clinical infections in pediatric patients over a 2-year period. The identification and susceptibility profiles were determined using an automated system. Isolates that suggested ESBL production based on their resistance profiles to third and fourth generation cephalosporin and monobactam were selected. ESBL production was phenotypically confirmed using a diffusion method with cefotaxime and ceftazidime discs alone and in combination with clavulanic acid. blaESBL gene identification was performed through PCR amplification and sequencing. Pulsed Field Gel Electrophoresis (PFGE) and Multilocus Sequence Typing (MLST) were performed to establish the clonal relationships of the E. coli isolates. CTX-M-9-type ESBLs were detected in 2.5% of the isolates. The subtypes corresponded to blaCTX-M-14 (n = 4) and blaCTX-M-27 (n = 6). Additionally, coexistence with other beta-lactamases was observed. A clonal relationship was established in three isolates; the rest were classified as non-related. We found seven different sequence type (ST) in CTX-M-9- producing E. coli isolates. ST38 was the most frequent. This study is the first report in Mexico to document the presence of group CTX-M-9 ESBLs in E. coli isolates from pediatric patients., Competing Interests: The authors have declared that no competing interests exist.

Extended-spectrum-cephalosporin-resistant Enterobacteriaceae are a public health concern due to limited treatment options. Here, we report on the occurrence and the molecular characteristics of extended-spectrum-cephalosporin-resistant Enterobacteriaceae recovered from wild birds (kelp gulls). Our results revealed kelp gulls as a reservoir of various extended-spectrum cephalosporinase genes associated with different genetic platforms. In addition, we report for the first time the presence of a known epidemic clone of Salmonella enterica serotype Heidelberg (JF6X01.0326/XbaI.1966) among wild birds., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

This report describes the first detection of a bla VEB-2 gene in a Vibrio parahaemolyticus strain isolated from a shrimp sample. The bla VEB-2 gene was carried on a novel Inc-type plasmid that was likely to have originated from aquatic organisms, as indicated by a comparison with other known genetic elements in the GenBank database. However, the plasmid contains resistance elements usually harbored by members of the family Enterobacteriaceae, suggesting that gene transfer events occurred and contributed to the formation of this multidrug resistance-encoding plasmid., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Resistance to extended-spectrum β-lactams in Salmonella, in particular, in serotypes such as Salmonella enterica serovar Enteritidis that are frequently associated with clinical infections, is a serious public health concern. In this study, phenotypic characterization of 433 clinical S. Enteritidis strains obtained from a nationwide collection of the Chinese Center for Disease Control and Prevention during the period from 2005 to 2010 depicted a trend of increasing resistance to ceftriaxone from 2008 onwards. Seventeen (4%) of the strains were found to be resistant to ceftriaxone, 7% were found to be resistant to ciprofloxacin, and 0.7% were found to be resistant to both ciprofloxacin and ceftriaxone. Most of the ceftriaxone-resistant S. Enteritidis strains (15/17) were genetically unrelated and originated from Henan Province. The complete sequence of an IncI1 plasmid, pSE115, which belonged to a novel sequence type, was obtained. This 87,255-bp IncI1 plasmid was found to harbor a blaCTX-M-14 gene in a novel multidrug resistance region (MRR) within the tra locus. Although the majority of strains were also found to contain conjugative IncI1 plasmids with a size similar to that of pSE115 (∼90 kb) and harbor a variety of blaCTX-M group 1 and group 9 elements, the novel MRR site at the tra locus in pSE115 was not detectable in the other IncI1 plasmids. The findings from this study show that cephalosporin resistance in S. Enteritidis strains collected in China was mainly due to the dissemination of IncI1 plasmids carrying blaCTX-M, resembling the situation in which IncI1 plasmids serve as major vectors of blaCTX-M variants in other members of the Enterobacteriaceae., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Invasive Salmonella infections (typhoidal and non-typhoidal) cause a huge burden of illness estimated at nearly 3.4 million cases and over 600,000 deaths annually especially in resource-limited settings. Invasive non-typhoidal Salmonella (iNTS) infections are particularly important in immunosuppressed populations especially in sub-Saharan Africa, causing a mortality of 20-30% in vulnerable children below 5 years of age. In these settings, where routine surveillance for antimicrobial resistance is rare or non-existent, reports of 50-75% multidrug resistance (MDR) in NTS are common, including strains of NTS also resistant to flouroquinolones and 3rd generation cephalosporins. Typhoid (enteric) fever caused by Salmonella Typhi and Salmonella Paratyphi A remains a major public health problem in many parts of Asia and Africa. Currently over a third of isolates in many endemic areas are MDR, and diminished susceptibility or resistance to fluoroquinolones, the drugs of choice for MDR cases over the last decade is an increasing problem. The situation is particularly worrying in resource-limited settings where the few remaining effective antimicrobials are either unavailable or altogether too expensive to be afforded by either the general public or by public health services. Although the prudent use of effective antimicrobials, improved hygiene and sanitation and the discovery of new antimicrobial agents may offer hope for the management of invasive salmonella infections, it is essential to consider other interventions including the wider use of WHO recommended typhoid vaccines and the acceleration of trials for novel iNTS vaccines. The main objective of this review is to describe existing data on the prevalence and epidemiology of antimicrobial resistant invasive Salmonella infections and how this affects the management of these infections, especially in endemic developing countries., (Copyright © 2015. Published by Elsevier Ltd.)

Background: Replacing oral treatments with ceftriaxone is a central component of public health efforts to slow the emergence of cephalosporin-resistant Neisseria gonorrhoeae in the United States; US gonorrhea treatment guidelines were revised accordingly in 2010. However, current US gonorrhea treatment practices have not been well characterized., Methods: Six city and state health departments in Cycle II of the STD Surveillance Network (SSuN) contributed data on all gonorrhea cases reported in 101 counties and independent cities. Treatment data were obtained through local public health surveillance and interviews with a random sample of patients. Cases were weighted to adjust for site-specific sample fractions and for differential nonresponse by age, sex, and provider type., Results: From 2010 to 2012, 135,984 gonorrhea cases were reported in participating areas, 15,246 (11.2%) of which were randomly sampled. Of these, 7,851 (51.5%) patients were interviewed. Among patients with complete treatment data, 76.8% received ceftriaxone, 16.4% received an oral cephalosporin, and 6.9% did not receive a cephalosporin; 51.9% of persons were treated with a regimen containing ceftriaxone and either doxycycline or azithromycin. Ceftriaxone treatment increased significantly by year (64.1% of patients in 2010, 79.3% in 2011, 85.4% in 2012; P = 0.0001). Ceftriaxone use varied widely by STD Surveillance Network site (from 44.6% to 95.1% in 2012)., Conclusions: Most persons diagnosed as having gonorrhea between 2010 and 2012 in the United States received ceftriaxone, and its use has increased since the release of the 2010 Centers for Disease Control and Prevention STD Treatment Guidelines.

Objectives: To determine the efficacy of daptomycin for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis using in vitro and in vivo methods., Methods: In vitro killing curves were determined with clinically achievable CSF antibiotic concentrations. In a rabbit model of pneumococcal meningitis, we studied the efficacy (Δ cfu/mL) of daptomycin used at 15 and 25 mg/kg, comparing it with ceftriaxone 100 mg/kg/24 h and ceftriaxone plus vancomycin 30 mg/kg/24 h over a 26 h period against two different strains: HUB 2349 and ATCC 51916, with MICs of 2 and 32 mg/L of cefotaxime/ceftriaxone, respectively., Results: The penetration of daptomycin into CSF ranged between 9% and 11%. Daptomycin therapy achieved an excellent response, being bactericidal within 2 h of antibiotic administration. Against strain HUB 2349, daptomycin at both doses was as effective as ceftriaxone plus vancomycin. Against the highly resistant strain, daptomycin 25 mg/kg was significantly better than ceftriaxone plus vancomycin at 2 and 6 h., Conclusions: Daptomycin at standard doses, and especially at high doses, may be a useful alternative for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: The proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to extended-spectrum cephalosporins (ESCs) has increased rapidly since 2006. Clinicians, researchers, and public health officials need to be prepared for the possibility of an era of untreatable gonorrhea. This review focuses on the evidence for current gonorrhea treatment recommendations, potential future treatment options, and other methods to control gonorrhea., Recent Findings: In addition to an increase in isolates with decreased susceptibility to ESCs, there have been reported treatment failures to both cefixime and ceftriaxone. In response, some countries have increased the recommended cephalosporin dose, and most now recommend dual therapy with an ESC and azithromycin. The pharynx has been implicated as a site for acquiring resistance through transformation with commensal Neisseria species or induced resistance through subtherapeutic antimicrobial levels. Thus, appropriate screening of the pharynx and treatment with a regimen that eradicates gonorrhea from the pharynx is necessary. At present, several studies are evaluating various novel treatment regimens in preparation for an era of untreatable gonorrhea., Summary: Screening for asymptomatic infections, maintaining culture capacity to monitor antimicrobial resistance, treating with ceftriaxone and azithromycin, and ensuring that all sexual partners are treated are among the best strategies to control gonorrhea in the current clime.

Enterococci are ubiquitous inhabitants of the gastrointestinal (GI) tract. However, antibiotic-resistant enterococci are also major causes of hospital-acquired infections. Enterococci are intrinsically resistant to cephalosporins, enabling growth to abnormally high densities in the GI tract in patients during cephalosporin therapy, thereby promoting dissemination to other sites where they cause infection. Despite its importance, many questions about the underlying basis for cephalosporin resistance remain. A specific two-component signaling system, composed of the CroS sensor kinase and its cognate response regulator (CroR), is required for cephalosporin resistance in Enterococcus faecalis, but little is known about the factors that control this signaling system to modulate resistance. To explore the signaling network in which CroR participates to influence cephalosporin resistance, we employed a protein fragment complementation assay to detect protein-protein interactions in E. faecalis cells, revealing a previously unknown association of CroR with the HPr protein of the phosphotransferase system (PTS) responsible for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses indicate that association with HPr restricts the ability of CroR to promote cephalosporin resistance and gene expression in a nutrient-dependent manner. Mutational analysis suggests that the interface used by HPr to associate with CroR is distinct from the interface used to associate with other cellular partners. Our results define a physical and functional connection between a critical nutrient-responsive signaling system (the PTS) and a two-component signaling system that drives antibiotic resistance in E. faecalis, and they suggest a general strategy by which bacteria can integrate their nutritional status with diverse environmental stimuli.

Tigecycline is a new glycylcyclin with a wide spectre including multi-resistant bacteria. Our laboratory tests in routine the in vitro activity of the TGC towards clinically significant isolates of 3rd generation cephalosporins resistant enterobacteriaceae (EC3R), Acinetobacter baumannii and Bacteroides fragilis group (BFG). The objective of this study is to describe the in vitro activity of TGC against these strains isolated between 2008 and 2011 in the university hospital of Montpellier. In this study period, 1070 isolates EC3R including 541 extended spectrum β-lactamase-producers (ESBL) strains, 47 isolates of A. baumannii including 40 multi-resistant isolates and 645 isolates of BFG were tested. Minimum inhibitory concentrations (MIC) were determined using the E-test method. TGC was active against 86.2% of EC3R with a MIC 90 less or equal to 1mg/L (Escherichia coli being the most sensitive species). A. baumannii and BFG were also inhibited at low concentrations of TGC with a MIC 90 less or equal to 2mg/L respectively for 47% and 84.2% of the isolates. Our study confirms the activity of TGC against the EC3R including ESBL-producers strains. The relevance of the therapeutic use of TGC on the BFG isolates with a MIC greater than 2mg/L should be better documented. Often prescribed in therapeutic impasse, the proper use of TGC would require: clarifying the threshold of sensitivity for some species (i.e., A. baumannii, Bacteroides fragilis group); a better understanding of correlation between in vitro and in vivo activity., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A screening of antimicrobial resistance and its genetic determinants has been performed on 300 Salmonella enterica isolates collected during 2004-2008 from human infections in Spain. Salmonella Typhimurium and Salmonella Enteritidis were the major serotypes, which were found with similar frequencies covering 80% of the bacterial collection. Salmonella Typhimurium isolates frequently shared low susceptibility to antimicrobials of the penta-resistance phenotype (ACSSuT) and/or cephalosporin resistance. The ACSSuT profile was found closely linked to int1-associated gene cassettes, with major elements carrying DNA fragments of 1.0 Kb (aadA2 gene) plus 1.2 Kb (blaPSE-1 gene) or 2.0 Kb (aadA1 and blaOXA-1 genes). Among these, ACSSuT and cephalosporin resistances were associated in Salmonella Typhimurium isolates expressing the blaOXA gene. β-lactamase activities were also detected from isolates carrying blaTEM, blaCMY, or blaSHV, although only the two last genes expressed extended-spectrum β-lactamases. The clonal analysis of S. enterica strains suggests that both horizontal and vertical transfer mechanisms are involved in the wide dissemination of their antimicrobial resistance.

The spreading of antimicrobial-resistant bacteria and genes from food-producing animals to humans has been a subject of increasing concern. To clarify the role of flies in spreading the extended-spectrum β-lactamase (ESBL) gene from food-producing animals to humans, we isolated and characterized a third-generation cephalosporin-resistant Escherichia coli strain from flies and cattle feces from a cattle barn. Cephalosporin-resistant strains were isolated from 14.3% (13/91) of houseflies, 10.3% (7/68) of false stable flies, and 7.5% (7/93) of cattle feces. Twenty-seven cephalosporin-resistant strains were tested for the presence of antimicrobial resistance genes. Of the 27 samples, 22 isolates from 11 houseflies, 5 false stable flies, and 6 cattle feces samples harbored the blaCTX-M-15 gene. All blaCTX-M-15-harboring isolates belonged to phylogenetic group D and the ST38 clonal group. Analysis of pulsed-field gel electrophoresis showed that these isolates were divided into two clusters, indicating that flies carried several of the same clones that were detected in cattle feces. All blaCTX-M-15 gene-harboring plasmids were transferable and were members of incompatibility group FIB. These results suggest that transferable plasmids encoding ESBL were prevalent among flies and cattle. As vectors, flies may play an important role in spreading ESBL-producing bacteria from food-producing animals to humans.

Broad-spectrum cephalosporin (BSC) resistance has increased in Escherichia coli isolates from broiler chickens in Japan since 2004. The purpose of this study was to understand the epidemiology of BSC-resistant E. coli in livestock animals. Among 3274 E. coli isolates from 1767 feces of apparently healthy animals on 1767 farms between 2004 and 2009, 118 ceftiofur (CTF)-resistant isolates (CTF MIC ≥4 μg/mL) were identified on 74 farms. After elimination of apparently clonal isolates from a single animal, 75 selected CTF-resistant isolates (62 isolates from 61 broiler chickens, 10 isolates from 10 layer chickens, two isolates from two cows, and one isolate from a pig) were characterized. The bla(CMY-2) gene was most frequently detected in 50 isolates, followed by bla(CTX-M) (CTX-M-2: six isolates; CTX-M-14: four isolates; CTX-M-25: two isolates; CTX-M-1: one isolate) and bla(SHV) (SHV-12: seven isolates; SHV-2, SHV-2a, SHV-5: one isolate each). In particular, 42 of 62 broiler chicken isolates harbored bla(CMY-2). Pulsed-field gel electrophoresis analyses using XbaI revealed divergent profiles among the BSC-resistant isolates. The incompatibility groups of bla(CMY-2) plasmids from 34 of the 42 broiler chicken isolates belonged to IncIγ (10 isolates), IncA/C (nine isolates), IncB/O (seven isolates) and IncI1 (six isolates), or were nontypeable (two isolates). Co-transmission of resistance to non-β-lactam antibiotics was observed in transconjugants with IncA/C plasmids, but not with IncI1, IncIγ, and IncB/O plasmids except for one isolate with IncB/O. Our findings suggest that the bla(CMY-2) gene is a key player in BSC-resistant E. coli isolates and that coselection is unlikely to be associated with the abundance of bla(CMY-2) plasmids, except for IncA/C plasmids.

Objectives: To characterize the mechanisms of fluoroquinolone and cephalosporin resistance in Enterobacteriaceae from a Dutch teaching hospital in 2008., Methods: We sequenced gyrA, gyrB, parC and parE. The presence of plasmid-encoded genes qnrA, qnrB, qnrS, aac(6')-Ib, qepA, bla(TEM), bla(SHV,) bla(OXA), bla(CTX-M) and bla(AmpC) was studied by PCR. Escherichia coli isolates were further characterized by AFLP and multilocus sequence typing (MLST)., Results: In total, 49 E. coli, 16 Klebsiella pneumoniae and 3 Enterobacter cloacae isolates were investigated. Mutations in gyrA were found in all E. coli isolates. Forty-five (92%) E. coli isolates carried at least one point mutation in parC. Most E. coli isolates (59%) also carried mutations in parE, of which I529L was the most prevalent. I529L was unequivocally associated with E. coli sequence type (ST) 131. This single-nucleotide polymorphism (SNP) was later also found in eight out of nine ST131 strains from another collection. Twenty-nine E. coli isolates carried extended-spectrum β-lactamase (ESBL) genes, predominantly bla(CTX-M-15). In E. coli, aac(6')-Ib-cr was the predominant plasmid-mediated resistance mechanism, whereas in K. pneumoniae qnr genes were found mostly. In K. pneumoniae isolates, qnr and aac(6')-Ib-cr co-occurred with ESBL genes (n = 13; bla(CTX-M) and bla(SHV)) and/or bla(AmpC) (n = 3; bla(DHA-1))., Conclusions: E. coli ST131 was the predominant clone, which accumulated a high number of chromosomal mutations. The I529L SNP in parE was a signature of most, but not all, ST131 strains. In contrast to E. coli, fluoroquinolone resistance mechanisms were predominantly plasmid-encoded in K. pneumoniae.

There is concern that a relationship exists between antibiotic use in livestock production and the emergence, spread, and persistence of antibiotic resistance. It is important to understand the impact that therapeutic doses of antibiotics for treatment of disease have on resistance because disease treatment typically involves higher doses of antibiotic over short time spans. Absolute quantities of the antibiotic resistance gene bla(CMY-2) were measured by real-time quantitative polymerase chain reaction (qPCR) in the bacterial community DNA of fecal samples from dairy cattle that were given a 5-day course of ceftiofur and untreated cattle during a longitudinal, observational study. A hierarchical linear model that accounts for left-censored data and repeated measures was used to estimate group means of bla(CMY-2) from the qPCR data. Ceftiofur-treated animals had significantly higher mean quantities of bla(CMY-2) than untreated animals during treatment. On the first day post-treatment, mean quantities of bla(CMY-2) returned to pre-treatment levels and remained low in both groups for the remainder of the study. The use of qPCR to measure bla(CMY-2) quantities provided evidence that the burden of resistance in treated animals may have increased temporarily, a result that was not evident when using only cultivation-based methods of testing for resistance.

The recent emergence of Neisseria gonorrhoeae strains with decreased susceptibility to extended-spectrum cephalosporins is a major concern globally. We sequenced the genome of an N. gonorrhoeae multiantigen sequence typing (NG-MAST) ST1407 isolate (SM-3) with decreased susceptibility and resistance to oral extended-spectrum cephalosporins. The isolate was cultured in 2008 in San Francisco, CA, and possessed mosaic penA allele XXXIV, which is associated with an international clone that possesses decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins globally. The genome sequence of strain NCCP11945 was used as a scaffold, and our assembly resulted in 91 contigs covering 2,029,064 bp (91%; >150× coverage) of the genome. Numerous instances of suspected horizontal genetic transfer events with other Neisseria species were identified, and two genes, opa and txf, acquired from nongonococcal Neisseria species, were identified. Strains possessing mosaic penA alleles (n = 108) and nonmosaic penA alleles (n = 169) from the United States and Europe (15 countries), cultured in 2002 to 2009, were screened for the presence of these genes. The opa gene was detected in most (82%) penA mosaic-containing isolates (mainly from 2007 to 2009) but not in any penA nonmosaic isolates. The txf gene was found in all strains containing opa but also in several (18%) penA nonmosaic strains. Using opa and txf as genetic markers, we identified a strain that possesses mosaic penA allele XXXIV, but the majority of its genome is not genetically related to strain SM-3. This implies that penA mosaic allele XXXIV was transferred horizontally. Such isolates also possessed decreased susceptibility and resistance to oral extended-spectrum cephalosporins. These findings support that genetic screening for particular penA mosaic alleles can be a valuable method for tracking strains with decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins worldwide and that screening using only NG-MAST may not be sufficient.

Enterococcus faecalis is a low-GC Gram-positive bacterium that is intrinsically resistant to cephalosporins, antibiotics that target cell wall biosynthesis. To probe the mechanistic basis for intrinsic resistance, a library of transposon mutants was screened to identify E. faecalis strains that are highly susceptible to ceftriaxone, revealing a transposon mutant with a disruption in murAA. murAA is predicted to encode a UDP-N-acetylglucosamine 1-carboxyvinyl transferase that catalyzes the first committed step in peptidoglycan synthesis: phosphoenolpyruvate (PEP)-dependent conversion of UDP-N-acetylglucosamine to UDP-N-acetylglucosamine-enolpyruvate. In-frame deletion of murAA, but not its homolog in the E. faecalis genome (murAB), led to increased susceptibility of E. faecalis to cephalosporins. Furthermore, expression of murAA enhanced cephalosporin resistance in an E. faecalis mutant lacking IreK (formerly PrkC), a key kinase required for cephalosporin resistance. Further genetic analysis revealed that MurAA catalytic activity is necessary but not sufficient for this role. Collectively, our data indicate that MurAA and MurAB have distinct roles in E. faecalis physiology and suggest that MurAA possesses a unique property or activity that enables it to enhance intrinsic resistance of E. faecalis to cephalosporins.

A total of 47 extended-spectrum-cephalosporin-resistant Escherichia coli strains isolated from stray dogs in 2006 and 2007 in the Republic of Korea were investigated using molecular methods. Extended-spectrum β-lactamase (ESBL) and AmpC β-lactamase phenotypes were identified in 12 and 23 E. coli isolates, respectively. All 12 ESBL-producing isolates carried bla(CTX-M) genes. The most common CTX-M types were CTX-M-14 (n = 5) and CTX-M-24 (n = 3). Isolates producing CTX-M-3, CTX-M-55, CTX-M-27, and CTX-M-65 were also identified. Twenty-one of 23 AmpC β-lactamase-producing isolates were found to carry bla(CMY-2) genes. TEM-1 was associated with CTX-M and CMY-2 β-lactamases in 4 and 15 isolates, respectively. In addition to bla(TEM-1), two isolates carried bla(DHA-1), and one of them cocarried bla(CMY-2). Both CTX-M and CMY-2 genes were located on large (40 to 170 kb) conjugative plasmids that contained the insertion sequence ISEcp1 upstream of the bla genes. Only in the case of CTX-M genes was there an IS903 sequence downstream of the gene. The spread of ESBLs and AmpC β-lactamases occurred via both horizontal gene transfer, accounting for much of the CTX-M gene dissemination, and clonal spread, accounting for CMY-2 gene dissemination. The horizontal dissemination of bla(CTX-M) and bla(CMY-2) genes was mediated by IncF and IncI1-Iγ plasmids, respectively. The clonal spread of bla(CMY-2) was driven mainly by E. coli strains of virulent phylogroup D lineage ST648. To our knowledge, this is the first report of bla(DHA-1) in E. coli strains isolated from companion animals. This study also represents the first report of CMY-2 β-lactamase-producing E. coli isolates from dogs in the Republic of Korea.

Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 μg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 μg/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥ 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤ 0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ≤ 0.002], SP 90 [-5.26 log(10) CFU/ml, P ≤ 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.

Recently, the first Neisseria gonorrhoeae strain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA, mtrR, penB, ponA, and pilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC = 4 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/ml) and resistance to most other antimicrobials examined. A novel penA mosaic allele (penA-CI), which was penA-XXXIV with an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains. N. gonorrhoeae appears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESC-resistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.

Shigellosis is a major cause of diarrheal diseases among children in Andaman & Nicobar Islands, India, which have a population of 350,000 people, including settlers from mainland India and 6 indigenous tribes. From the last one-and-half decade, we have been monitoring the species distribution and emergence of antibiotic resistance among the isolates of Shigella. The circulating Shigella strains have been found rapidly acquiring resistance to a wide spectrum of antibiotics. The recent data indicate that a significant proportion of Shigella isolates have been resistant to newer generation of cephalosporins, which are used as an alternative of quinolones to treat the patients with shigellosis. In this communication, we report the antibiotic-resistant pattern of Shigella isolates that are recently isolated from these islands. From January 2008 to December 2009, 311 stool samples were processed and 44 (14%) Shigella isolates were recovered. Out of these 44 Shigella isolates, 6 (14%) were found to be resistant to all the three third-generation cephalosporins tested. The minimum inhibitory concentrations of the resistant isolates were all above the breakpoint for reduced susceptibility as per the Clinical and Laboratory Standards Institute guidelines. All of the cephalosporin-resistant Shigella strains were confirmed to produce extended-spectrum β-lactamases. By analyzing trends in the resistance patterns of the various Shigella species, we found that Shigella dysenteriae (40%) is currently more resistant, followed by Shigella flexneri (14%), than the other Shigella species in these islands of India, especially to the third-generation cephalosporins. The acquisition of resistance by enteric pathogens to the increasing number of antibacterial drugs is becoming a grave concern, particularly in developing countries where shigellosis is of a common occurrence.

This study evaluates the efficacy of eight different cephalosporins for detection of cephalosporin resistance mediated by extended spectrum beta-lactamases (ESBL) and plasmidic AmpC beta-lactamases in Salmonella and Escherichia coli. A total of 138 E. coli and 86 Salmonella isolates with known beta-lactamase genes were tested for susceptibility toward cefoperazone, cefotaxime, cefpodoxime, cefquinome, ceftazidime, ceftiofur, ceftriaxone, and cefuroxime using minimum inhibitory concentration determinations and disc diffusion. The collection consisted of 84 ampicillin-susceptible, 57 ampicillin-resistant but cephalosporin-susceptible, 56 ESBL isolates and 19 isolates with plasmidic AmpC, as well as 10 ampC hyper-producing E. coli. The minimum inhibitory concentration distributions and zone inhibitions varied with the tested compound. Ampicillin-resistant isolates showed reduced susceptibility to the cephalosporins compared to ampicillin-susceptible isolates. Cefoperazone, cefquinome, and cefuroxime were not useful in detecting isolates with ESBL or plasmidic AmpC. The best substances for detection were cefotaxime, cefpodoxime, and ceftriaxone, whereas ceftazidime and ceftiofur were not as efficient. Ceftriaxone may be the recommended substance for monitoring because of some ability in separating ampC hyper-producing E. coli from ESBL and plasmidic AmpC isolates.

The present work was undertaken to study the ability of ceftazidime and ceftibuten to selectin vitro Escherichia coli HB101 harboring bla(TEM-1) beta-lactamase gene. Minimum inhibitory concentrations (MICs) of ceftazidime and ceftibuten were increased by a factor of 32, overcoming in the case of ceftazidime the breakpoint for clinical resistance. Outer membrane protein analysis and PCR for bla(TEM )alleles revealed that ceftazidime and ceftibuten select for different resistance mechanisms. Ceftazidime created mutants that encode an extended-spectrum beta-lactamase (TEM-12) and exhibit decreased expression of OmpF. Ceftibuten was unable to select for extended-spectrum beta-lactamase expressing mutants but reduced the expression of two porins, OmpC and OmpF. The stability of ceftibuten to hydrolysis and the difference in the structure of these beta-lactam antibiotics could be responsible for the selection of different mechanisms of resistance.

The link between administration of antibiotics and detection of third-generation-cephalosporin-resistant (TGCR) enterobacteriaceae in faeces was studied in patients in a burns intensive care unit (ICU). The presence of extended-spectrum beta-lactamase producers was also determined in these isolates. At least two rectal swab samples were taken from 43 of 72 patients admitted to the ICU from January 1998 to June 1999. Antibiotic resistance tests were performed for all isolated enterobacteriaceae using the methods of the National Committee for Clinical Laboratory Standards. Only 10 out of 30 antibiotic-treated patients showed TGCR enterobacteriaceae in faeces. Fisher's exact test showed a relationship between the administration of oxyiminocephalosporins (third-generation cephalosporins) (P=0.002) or carbapenems (P=0.003) and the isolation of TGCR enterobacteriaceae from faeces. The administration of oxyiminocephalosporins led to the selection of resistant strains in the faecal flora.

Objectives: To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L)., Methods: Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h., Results: Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin., Conclusions: Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.

In a matched case-control study, we studied the effect of prior receipt of fluoroquinolones on isolation of three third-generation cephalosporin-resistant gram-negative nosocomial pathogens. Two hundred eighty-two cases with a third-generation cephalosporin-resistant pathogen (203 with Enterobacter spp., 50 with Pseudomonas aeruginosa, and 29 with Klebsiella pneumoniae) were matched on length of stay to controls in a 1:2 ratio. Case-patients and controls were similar in age (mean 62 years) and sex (54% male). Variables predicting third-generation cephalosporin resistance were surgery (p = 0.005); intensive care unit stay (p < 0.001); and receipt of a b-lactam/b-lactamase inhibitor (p < 0.001), a ureidopenicillin (p = 0.002), or a third-generation cephalosporin (p < 0.001). Receipt of a fluoroquinolone was protective against isolation of a third-generation cephalosporin-resistant pathogen (p = 0.005). Interventional studies are required to determine whether replacing third-generation cephalosporins with fluoroquinolones will be effective in reducing cephalosporin resistance and the effect of such interventions on fluoroquinolone resistance.