What were the risk factors and trends in antimicrobial resistance for enteric fever in London 2005-2012?

Purpose. A study was undertaken to determine the risk factors and trends in antimicrobial resistance for enteric fever.Methodology. Demographic, antimicrobial susceptibility, typing and epidemiological data were examined for 2005-2012 in patients with enteric fever in London. Single and multivariable logistic regression was used to determine the risk factors associated with antibiotic resistance.Results. 453 cases with Salmonella enterica subsp. enterica serovar Paratyphi A, 17 with S. Paratyphi B and 611 with S. enterica subsp. enterica serovar Typhi were examined. For travellers, 335 (88 %) of S. Paratyphi A isolates were resistant to ciprofloxacin, but resistance to other antimicrobials was low. Almost 80 % (395) of the S. Typhi isolates were resistant to ciprofloxacin, 131 (26 %) to ampicillin, 131 (27 %) to chloramphenicol, 137 (28 %) to trimethoprim and 171 (28 %) to sulphonamide. None of the isolates were resistant to cephalosporins.A trend analysis for S. Typhi isolates showed no significant change in resistance to ampicillin, chloramphenicol, sulphonamide and trimethoprim or for multidrug resistance (P=0.38). Overall resistance to ciprofloxacin increased for S. Paratyphi A (P=0.018) and for S. Typhi (P<0.001) but fell for S. Typhi in 2011-2012. Resistance profiles were reflected by specific phage types and countries visited by the travellers.Conclusions. The proportion of S. Typhi strains resistant to ampicillin, chloramphenicol and cotrimoxazole remained steady for the period 2005-2012. There was a significant increase in a trend for resistance to ciprofloxacin which increased until 2010, followed by a fall in 2011-2012. S. Paratyphi resistance to ciprofloxacin increased until 2012. Specific phage types were associated with resistance to specific antimicrobials and travel abroad.

An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid.

The population of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, exhibits limited DNA sequence variation, which complicates efforts to rationally discriminate individual isolates. Here we utilize data from whole-genome sequences (WGS) of nearly 2,000 isolates sourced from over 60 countries to generate a robust genotyping scheme that is phylogenetically informative and compatible with a range of assays. These data show that, with the exception of the rapidly disseminating H58 subclade (now designated genotype 4.3.1), the global S. Typhi population is highly structured and includes dozens of subclades that display geographical restriction. The genotyping approach presented here can be used to interrogate local S. Typhi populations and help identify recent introductions of S. Typhi into new or previously endemic locations, providing information on their likely geographical source. This approach can be used to classify clinical isolates and provides a universal framework for further experimental investigations.

Trends in antibiotic susceptibility of enteric fever isolates in East London.

BACKGROUND: The study sought evidence for changes in the proportions of antibiotic resistant strains among isolates of Salmonella enterica serovar Typhi (S. typhi) and Salmonella enterica serovar Paratyphi (S. paratyphi) between 2005 and 2012. METHODS: Blood culture isolates of S. typhi and S. paratyphi from patients attending Newham and The Royal London Hospitals were included in the study. The organisms were cultured on selective media and identified by Maldi-ToF, API 20E and serology. Minimum inhibitory concentrations (MICs) of augmentin, chloramphenicol, co-trimoxazole, ceftriaxone, ciprofloxacin and azithromycin were determined by E tests for 194 isolates. RESULTS: Median MICs of ciprofloxacin and ceftriaxone were stable at 0.5 mg/L and 0.125 mg/L, respectively. Chloramphenicol, azithromycin, co-trimoxazole and augmentin median MICs were 4 mg/L, 8 mg/L, 0.064 mg/L and 0.5 mg/L, respectively. MIC90 values were lower than the resistant breakpoint for ceftriaxone, azithromycin and augmentin, but were >256 mg/L for chloramphenicol, 32 mg/L for co-trimoxazole and 1 mg/L for ciprofloxacin. CONCLUSIONS: Antibiotic resistance remained stable for enteric fever isolates between 2005 and 2012. The isolates remained susceptible to augmentin, ceftriaxone and azithromycin over this period, but the MIC90 was greater than the resistant breakpoint for chloramphenicol, cotrimoxazole and ciprofloxacin. The implications for clinical practice are that isolates of S. typhi and S. paratyphi from East London remain sensitive to ceftriaxone and azithromycin.

Enteric fever and its impact on returning travellers.

Enteric fever, a systemic illness, is caused by Salmonella enterica serovar Typhi or S. enterica serovar Paratyphi A, B or C. The organism is transmitted to humans by the faecal oral route and is endemic in countries with poor sanitation and lacking clean drinking water. There are around 27 million individuals infected with S. Typhi worldwide annually. Enteric fever is a particular problem in travellers to endemic areas, especially those visiting friends and relatives. Currently, the two main vaccines recommended for travellers are the Vi polysaccharide vaccine and the oral Ty21a vaccine. These internationally licensed vaccines are safe and effective against S. Typhi. However, there is currently no commercially available vaccine against S. Paratyphi, which is increasingly reported as a cause of enteric fever. Vaccine uptake and taking appropriate precautions are poor in travellers visiting friends and relatives abroad; this problem requires addressing. Ciprofloxacin is no longer recommended for empirical treatment of infection because of increasing reports of resistance, especially from South Asia. Ceftriaxone and azithromycin are currently the most commonly used antimicrobials for empirical treatment of enteric fever but resistance to both these agents is emerging.

East London experience with enteric fever 2007-2012.

PURPOSE: The clinical presentation and epidemiology for patients with enteric fever at two hospitals in East London during 2007-2012 is described with the aim to identify preventive opportunities and to reduce the cost of treatment. METHODS: A retrospective analysis of case notes from patients admitted with enteric fever during 2007 to 2012 with a microbiologically confirmed diagnosis was undertaken. Details on clinical presentation, travel history, demographic data, laboratory parameters, treatment, patient outcome and vaccination status were collected. RESULTS: Clinical case notes were available for 98/129 (76%) patients including 69 Salmonella enterica serovar Typhi (S. Typhi) and 29 Salmonella enterica serovar Paratyphi (S. Paratyphi). Thirty-four patients (35%) were discharged from emergency medicine without a diagnosis of enteric fever and then readmitted after positive blood cultures. Seventy-one of the 98 patients (72%) were UK residents who had travelled abroad, 23 (23%) were foreign visitors/new entrants to the UK and four (4%) had not travelled abroad. Enteric fever was not considered in the initial differential diagnosis for 48/98 (49%) cases. The median length of hospital stay was 7 days (range 0-57 days). The total cost of bed days for managing enteric fever was £454,000 in the two hospitals (mean £75,666/year). Median time to clinical resolution was five days (range 1-20). Seven of 98 (7%) patients were readmitted with relapsed or continued infection. Six of the 71 (8%) patients had received typhoid vaccination, 34 (48%) patients had not received vaccination, and for 31 cases (44%) vaccination status was unknown. CONCLUSIONS: Further interventions regarding education and vaccination of travellers and recognition of the condition by emergency medicine clinicians in travellers to South Asia is required.

Epidemiology, antibiotic resistance trends and the cost of enteric fever in East London, 2005-2010.

INTRODUCTION: Enteric fever seen in the UK has usually been acquired abroad. The cost to the NHS of treating enteric fever cases is not known. Data on the epidemiology of enteric fever, inpatient treatment costs and the public health management is needed to make decisions regarding the cost benefit considerations of introducing targeted prevention strategies. METHODS: A retrospective study of laboratory confirmed enteric fever cases was conducted to estimate the cost of inpatient treatment and to determine antimicrobial resistance patterns at two hospitals in East London between January 2005 and the end of August 2010. RESULTS: 138 cases of enteric fever were identified during the study period (90 S.ser.Typhi and 48 S. ser. Paratyphi). 92% had a recent history of foreign travel, 57% had travelled to visit friends and relatives (VFRs), 26% sought pre-travel health advice and 26% of patients had received typhoid vaccination. The inpatient treatment cost of 138 cases to the NHS was £272,747. The proportion of isolates with high level ciprofloxacin resistance (MICs>1 mg/L) has increased from 10% in 2006 to 30% in 2010. Our data also shows the emergence of isolates with high azithromycin MICs (>32 mg/L); 60% (six out of ten) isolates tested in July-August 2010. CONCLUSIONS: There is a significant direct cost of treating enteric fever cases on the NHS. Cost reduction measures are confined due to the lack of effective oral antibiotics following the emergence of high level resistance to ciprofloxacin and azithromycin. Outpatient parenteral antibiotic therapy service and improved preventative public health measures aimed at VFR travellers in particular may be helpful in reducing costs.

Evaluation of azithromycin, trovafloxacin and grepafloxacin as prophylaxis for experimental murine melioidosis.

The efficacies of the azalide azithromycin and the fluoroquinolones trovafloxacin and grepafloxacin for pre- and post-exposure prophylaxis of infection with high or low challenge doses of Burkholderia pseudomallei strain 576 were assessed in an experimental mouse model. Trovafloxacin and grepafloxacin afforded significant levels of protection, whereas azithromycin was ineffective and potentially detrimental. Overall, the data suggest that some fluoroquinolones may have potential utility in prophylaxis of melioidosis and suggest that azithromycin would not be effective in prophylaxis of B. pseudomallei infection.

Evaluation of azithromycin, trovafloxacin and grepafloxacin as prophylaxis against experimental murine Brucella melitensis infection.

The prophylactic potential of the azalide azithromycin as well as the fluoroquinolones trovafloxacin and grepafloxacin was assessed for the control of infection with Brucella melitensis in an experimental mouse model, determined by reduction in splenic bacterial burden. Trovafloxacin showed limited protective efficacy when administered 2h following a low-dose B. melitensis challenge, whereas grepafloxacin was ineffective. In comparison, azithromycin provided significant control of infection both following low- and high-dose challenges. Overall, the data confirm the potential utility of azithromycin in the prophylaxis of brucellosis and suggest that neither trovafloxacin nor grepafloxacin would likely be valuable for post-exposure prophylaxis of Brucella infection.

Gemella morbillorum: an underestimated aetiology of central nervous system infection?

A case is reported of cerebellar abscess and diffuse cerebritis due to Gemella morbillorum. The clinical course was 'biphasic', developing with an acute meningeal infection followed shortly afterwards by suppuration in the cerebellar and cerebral parenchyma; this pattern seemed to suggest a latent survival of the aetiological agent, probably within the central nervous system (CNS), despite systemic antibiotic therapy. Based upon a review of cases so far described, infections of the CNS caused by G. morbillorum appear to be an emerging reality.

High throughput identification of clinical isolates of Staphylococcus aureus using MALDI-TOF-MS of intact cells.

Staphylococcus aureus remains an important human pathogen responsible for a high burden of disease in healthcare and community settings. The emergence of multidrug-resistant strains is of increasing concern world-wide. The identification of S. aureus is currently based upon phenotypic and genotypic methods. Here, an alternative approach involving mass spectral analysis of surface-associated proteins of intact bacterial cells by matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF-MS) was investigated using 95 isolates obtained directly from a clinical laboratory at The Royal London Hospital and 39 isolates from the Staphylococcal Reference Unit, Health Protection Agency, London. Results obtained indicate that clinical isolates share many common mass ions with-type/reference strains which allowed their correct identification when searched against a comprehensive database that has been in the process of development for several years. The existing database contains more than 5000 profiles of various bacterial pathogens, but comprises mainly type or reference strains. The MicrobeLynx software successfully identified all isolates to the correct genus and all but four to the correct species. These were misidentified in the first instance due to contamination or low mass ion intensity but once the cultures were purified and re-analysed they were confirmed as S. aureus by both MALDI-TOF-MS and 16S rRNA sequence analysis. The high percentage of correct identifications coupled with the high speed and the minimal sample preparation required, indicate that MALDI-TOF-MS has the potential to perform high throughput identification of clinical isolates of S. aureus despite the inherent diversity of this species. The method is, however, only reproducible if variable parameters such as sample preparation, media, growth condition, etc. are standardised.

Staphylococcus caprae meningitis following intraspinal device infection.

A case is reported of Staphylococcus caprae meningitis due to infection of an intraspinal analgesia pump. The subclinical and pauci-symptomatic clinical course of the infection strongly suggested a chronic device contamination.

A rapid microplate method for quantifying inhibition of bacterial adhesion to eukaryotic cells.

Adhesion of bacteria to the mucosal epithelial cell surface is the first step in infection, and studies have shown that inhibition of this step may be useful therapeutically. To test compounds that may prevent bacterial binding to a number of epithelial cell lines, we have developed a high-throughput adhesion assay using a microtitre plate system and bacteria that have been modified to express firefly luciferase. This method has proved to be a sensitive, rapid, and reproducible system for screening antiadhesive agents for their effects on bacterial adhesion.

Properties and potential of ertapenem.

Ertapenem is a carbapenem that shares the activity of imipenem and meropenem against most species, but is less active against non-fermenters. Activity is retained against most strains with AmpC and extended-spectrum beta-lactamases, although resistance can arise if these enzymes are combined with extreme impermeability. Resistance can also be caused by IMP, VIM, KPC and NMC carbapenemases, but again, co-requires impermeability. Although the spread of carbapenemases in the future is a concern, they are currently very rare. Given as a 1 g intravenous (iv) infusion once daily, ertapenem has a plasma half-life of approximately 4 h in healthy volunteers, and a Cmax of 155 mg/L and 13 mg/L for total and free drug, respectively. Excretion is largely renal, divided equally between native drug and an open-ring derivative. Trials show equivalence to piperacillin/tazobactam or ceftriaxone in (a) intra-abdominal infections, (b) community-acquired pneumonia, (c) acute pelvic infections, (d) skin and skin structure infections and (e) complicated urinary tract infections. The USA licence grants all these five indications; the EU licence grants the first three. Further potential uses include home iv therapy, directed therapy against Enterobacteriaceae with AmpC or extended-spectrum cephalosporinases, and tentatively, surgical prophylaxis. Widening the usage of carbapenems raises public health concerns, somewhat allayed by the continued rarity of carbapenemases after 17 years of imipenem use, and by the fact that carbapenemases occur mostly in non-fermenters outside the spectrum of ertapenem, and co-require impermeability to confer resistance in Enterobacteriaceae. Nevertheless, if ertapenem is to be used widely, its effects on the resistance ecology need to be monitored carefully.

Tsukamurella tyrosinosolvens intravascular catheter infection identified using 16S ribosomal DNA sequencing.

Cultures of blood from a hemodialysis line repeatedly yielded a gram-positive rod. The organism was identified as Tsukamurella tyrosinosolvens by 16S ribosomal DNA sequencing, and the patient was treated successfully by removal of the line.

New millennium antivirals against pandemic and epidemic influenza: the neuraminidase inhibitors.

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.

Mechanisms of antimicrobial resistance: their clinical relevance in the new millennium.

Antimicrobials show selective toxicity. Suitable targets for antimicrobials to act at include the bacterial cell wall, bacterial protein and folic acid synthesis, nucleic acid metabolism in bacteria and the bacterial cell membrane. Acquired antimicrobial resistance generally can be ascribed to one of five mechanisms. These are production of drug-inactivating enzymes, modification of an existing target, acquisition of a target by-pass system, reduced cell permeability and drug removal from the cell. Introduction of a new antimicrobial into clinical practice is usually followed by the rapid emergence of resistant strains of bacteria in some species that were initially susceptible. This has reduced the long-term therapeutic value of many antimicrobials. It used to be thought that antibacterial resistance was mainly a hospital problem but now it is also a major problem in the community. Organisms in which resistance is a particular problem in the community include members of the Enterobacteriaceae, including Salmonella spp. and Shigella spp., Mycobacterium tuberculosis, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria gonorrhoeae. Multi-resistant Gram-negative rods, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci are major causes of concern in the hospital setting. Prevalence of antibacterial resistance depends both on acquisition and spread. Decreasing inappropriate usage of antimicrobials should lessen the rate of acquisition, and spread can be minimised by sensible infection control measures.