Impact of a clonal outbreak of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae in the development and evolution of bloodstream infections by K. pneumoniae and Escherichia coli: an 11 year experience in Oxfordshire, UK.

OBJECTIVES: The objectives of this study were: (i) to describe an outbreak of multidrug-resistant Klebsiella pneumoniae in our population; (ii) to identify the potential source of this outbreak by examining antibiotic resistance trends in urocultures; (iii) to evaluate the contribution of this outbreak to resistance patterns over time in the two commonest Gram-negative blood culture isolates, namely K. pneumoniae and Escherichia coli; and (iv) to assess risk factors for multidrug resistance and the impact of this resistance on mortality and length of stay. METHODS: We searched Microbiology and Patient Administration Service databases retrospectively and describe resistance trends in E. coli and K. pneumoniae bloodstream infections (BSIs) in Oxfordshire, UK, over an 11 year period. RESULTS: An outbreak of a multidrug-resistant, CTX-M-15 extended-spectrum ß-lactamase (ESBL)-producing K. pneumoniae clone was identified and shown by multilocus sequence typing to belong to a novel sequence type designated ST490. This was associated with a sporadic change in resistance rates in K. pneumoniae BSIs with rates of multidrug resistance (defined as resistance to three or more antibiotic classes) reaching 40%. A case-control study showed prior antibiotic exposure as a risk factor for infection with this organism. During the same time period, rates of ESBL-producing Klebsiella spp. isolated from urocultures increased from 0.5% to almost 6%. By contrast, the rate of multidrug resistance in E. coli rose more steadily from 0% in 2000 to 10% in 2010. CONCLUSIONS: Changes in resistance rates may be associated with outbreaks of resistant clones in K. pneumoniae. Changing resistance patterns may affect important health economic issues such as length of stay.

Study of antibiotic prescribing among dental practitioners in Shiraz, Islamic Republic of Iran.

Inappropriate prescribing of antibiotics by health care professionals is a worldwide concern. This study evaluated the knowledge and practices of dental practitioners in the city of Shiraz, Islamic Republic of Iran regarding their therapeutic use of antibiotics for patients with dentoalveolar infections. Of 219 (48.6%) dentists responding to the questionnaire more than 40% would prescribe antibiotics for localized fluctuant swelling and for problems for which antibiotics are not required according to good practice guidelines (acute pulpitis, chronic apical infection, periodontal abscess, chronic gingivitis, chronic periodontitis, pericoronitis and dry socket). A majority correctly prescribed antibiotics for acute periapical infection (77.2%), cellulitis (75.3%) and acute ulcerated gingivitis (63.0%). Amoxicillin was the most frequently prescribed antibiotic for all clinical conditions but there was a wide variation in dosage, frequency and duration for all antibiotics used. Guidelines on rational antibiotic use are needed for dental practitioners in the Islamic Republic of Iran.

Correlation between meticillin-resistant Staphylococcus aureus prevalence and infection control initiatives within southern and eastern Mediterranean hospitals.

The Mediterranean region has been identified as an area of hyper-endemicity for multi-resistant hospital pathogens. To better understand potential drivers behind this situation, we attempted to correlate already published meticillin-resistant Staphylococcus aureus (MRSA) data from 27 hospitals, participants in the Antibiotic Resistance Surveillance & Control in the Mediterranean Region (ARMed) project, with responses received from the same institutions to questionnaires which dealt with various aspects of infection control and antibiotic stewardship. No difference could be ascertained between high and low prevalence hospitals in terms of scores from replies to structured questions regarding infection control set-up, hand hygiene facilities and antibiotic stewardship practices. However, we did identify differences in terms of bed occupancy and isolation facilities. Hospitals reporting frequent episodes of overcrowding, particularly involving several departments, and which found regular difficulties sourcing isolation beds, had significantly higher MRSA proportions. This suggests that infrastructural deficits related to insufficient bed availability and compounded by inadequate isolation facilities could potentiate MRSA hyper-endemicity in south-eastern Mediterranean hospitals.

Clinical and molecular epidemiology of ciprofloxacin-susceptible MRSA encoding PVL in England and Wales.

We aimed to enhance our case ascertainment of meticillin-resistant Staphylococcus aureus encoding Panton-Valentine leucocidin (PVL-MRSA), determine the patient demographic, risk factor and disease associations, and define the clonal diversity amongst isolates referred to the UK Health Protection Agency's Staphylococcus Reference Unit. PVL-MRSA collected during 2005-6 from community-based and hospitalised patients located across England and Wales were identified by polymerase chain reaction (PCR). Representative geographically and temporally unrelated isolates were characterised via toxin gene profiling, SCCmec, spa and agr typing, multilocus sequence typing (MLST) and minimum inhibitory concentration (MIC) determinations. PVL-MRSA were identified from 275 patients. Affected individuals were <1 to 95 years of age (mean 30, median 27 years). Forty-five isolates were from 18 household or community-based clusters and 23 isolates were from outbreaks in healthcare settings. Overall, 58% (n = 161) had skin and soft tissue infections and 9% (n = 25) presented with or developed more serious disease, including eight patients (3%) with necrotising pneumonia, five of whom subsequently died. PVL-MRSA were genetically diverse and harboured SCCmecIV or V(T)/VII. Representatives of MLST clonal complexes (CCs) 8, 30 and 80 were identified the most often. The 275 PVL-MRSA included internationally disseminated community-associated MRSA (CA-MRSA) strains, as well as other minor lineages, and were associated with typical risk factors and disease presentations.

Infection control and antibiotic stewardship practices reported by south-eastern Mediterranean hospitals collaborating in the ARMed project.

The prevalence of multiply resistant organisms (MROs) reported from south-eastern Mediterranean hospitals highlights the need to identify possible contributory factors to help design control interventions. This was investigated through a structured questionnaire, which examined infection control and antibiotic stewardship practices in hospitals participating or collaborating with the Antibiotic Resistance SurveilLance & Control in the Mediterranean Region (ARMed) project. A total of 45 hospitals (78.9% of invited institutions) responded to the questionnaire; 60% indicated that they faced periods of overcrowding when available bed complement was insufficient to cope with hospital admissions and 62% reported difficulties in isolating patients with MROs due to lack of available beds. Most hospitals relied mainly on washing to achieve hand hygiene, whether by non-medicated or disinfectant soaps. Dependence on solid bars of soap (28.9%) and cloth towels (37.8%) were among the problems identified as well as inconvenient distances of sinks from patient beds (66.6%). Alcohol hand rub was the predominant hand hygiene product in only 7% of hospitals. Programmes for better antibiotic use were mostly limited in scope; 33.3% reported having antibiotic prescribing guidelines and 53.3% of hospitals fed back resistance rates to prescribers. Auditing of antibiotic consumption, whether institution- or unit-based, was carried out in 37.8% of responding hospitals. Multi-faceted approaches aimed at improving isolation of patients with MROs, increasing the emphasis on hand hygiene by encouraging greater use of alcohol hand rubs and introducing effective antibiotic stewardship programmes should be encouraged in south-eastern Mediterranean hospitals.

Survey of infection control infrastructure in selected southern and eastern Mediterranean hospitals.

A structured questionnaire concerning hospital infection control (IC) organisation and initiatives was sent to 45 hospitals in Algeria, Cyprus, Egypt, Jordan, Lebanon, Libya, Malta, Morocco, Tunisia and Turkey. Hospitals bordering the eastern Mediterranean appeared to have more established IC infrastructures than southern Mediterranean hospitals. However, there were no significant differences among hospitals in the two regions in surveillance activities, the presence of an antibiotic policy or feedback of resistance data to prescribers, all of which were at a low level. Only a minority of hospitals had published antimicrobial treatment guidelines or gave feedback on antimicrobial resistance data to prescribers.

Status of infection control policies and organisation in European hospitals, 2001: the ARPAC study.

Patient safety in hospital care depends on effective infection control (IC) programmes. The Antimicrobial Resistance Prevention and Control (ARPAC) study assessed the organisation, components and human resources of IC programmes in European hospitals. A questionnaire survey of policies and procedures implemented in 2001 for the surveillance and control of nosocomial infection and antibiotic resistance was completed by 169 acute-care hospitals from 32 European countries, categorised by five geographical regions. A formal IC programme existed in 72% of hospitals, and a multidisciplinary IC committee was operational in 90%. Trained IC nurses (ICNs) were present in 80% of hospitals (ranging from 54% in south-east and central-eastern Europe, to 100% in northern Europe), whereas 74% had one or more trained IC doctors (ICDs) (ranging from 46% in south-east Europe to 84% in western Europe). Median staffing levels were 2.33 ICNs/1,000 beds and 0.94 ICDs/1,000 beds. The intensity of IC programmes scored higher in centres from northern and western Europe than from other European regions. Written guidelines promoted hand hygiene for healthcare workers in 89% of hospitals, education in 85%, and audit in 46%. Guidelines recommended use of alcohol-based solutions (70%) and/or medicated/antiseptic soap (43%) for decontamination of non-soiled hands. Use of alcohol-based solutions varied according to region, from 41% in southern Europe to 100% in northern Europe, compared with use of medicated soap from 77% in southern Europe to 11% in northern Europe (p < 0.01). These findings showed that IC programmes in European hospitals suffer from major deficiencies in human resources and policies. Staffing levels for ICNs were below recommended standards in the majority of hospitals. Education programmes were incomplete and often not supported by audit of performance. Hand hygiene procedures were sub-standard in one-third of centres. Strengthening of IC policies in European hospitals should be a public health priority.

Guidelines for the control of glycopeptide-resistant enterococci in hospitals.

The increase since the mid 1980s in glycopeptide resistant enterococci (GRE) raised concerns about the limited options for antimicrobial therapy, the implications for ever-increasing numbers of immunocompromised hospitalised patients, and fuelled fears, now realised, for the transfer of glycopeptide resistance to more pathogenic bacteria, such as Staphylococcus aureus. These issues underlined the need for guidelines for the emergence and control of GRE in the hospital setting. This Hospital Infection Society (HIS) and Infection Control Nurses Association (ICNA) working party report reviews the literature relating to GRE prevention and control. It provides guidance on microbiological investigation, treatment and management, including antimicrobial prescribing and infection control measures. Evidence identified to support recommendations has been categorized. A risk assessment approach is recommended and areas for research and development identified.

Methicillin-resistant Staphylococcus aureus in the community: new battlefronts, or are the battles lost?

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of nosocomial infections worldwide. Interpretation of community MRSA trends is problematical, in that the term is ill-defined, and related data are difficult to put into context. There are four relevant battlefronts, all of interest to risk assessment and prevention. These comprise the following: the issues relating to an increasing pool of patients with MRSA discharged from hospitals into the community; MRSA spreading to patients in nursing and residential homes; and MRSA spreading from patients and healthcare workers to others in the community. There are often difficulties in determining whether the fourth issue, MRSA arising apparently de novo in the community, is in fact due to one of these other fronts. All these battlefronts are important and not yet lost. However, we must agree on definitions and design-appropriate surveillance strategies, so that we can best inform prevention and control activities to contain these emerged or emerging problems.

Screening for Corynebacterium diphtheriae.

A throat swab from a 9 year old girl with pharyngitis yielded a non-toxigenic strain of Corynebacterium diphtheriae var mitis and Streptococcus group G. C pseudodiphtheriticum was isolated from the throats of two of her four brothers. In each case the isolate was sent to the reference laboratory before full identification. The growth was found to be mixed for one brother; the other isolate being a toxin producing C diphtheriae var gravis. The child was asymptomatic and the case proves that all colonial types on the Hoyles plate should be identified.

Ribotyping of coagulase-negative staphylococci.

The discriminative capacity of ribotyping was initially assessed without knowledge of results obtained for the same isolates by use of more established typing methods. Forty-eight isolates of coagulase-negative staphylococci (CNS) from peritoneal fluids were studied. They were collected prospectively during 31 consecutive episodes of infection associated with peritoneal dialysis in 17 patients. DNA was digested by the restriction endonucleases EcoRI or HindIII and ribotyped by means of a biotinylated cDNA probe to 16S + 23S staphylococcal ribosomal RNA gene sequences. These methods in combination produced a total of 27 types which compared well with numbers of groups distinguished by other typing methods: limited biotype-antibiotic resistogram (ARB; 28), antibiotic resistogram alone (25), API-Staph (12), phage typing (9) and plasmid analysis (22). Ribotyping was highly reproducible and typed all isolates, including those that were not phage-typable (35) or did not contain plasmids (4). When used in a hierarchical manner with ARB, ribotyping results produced 13 additional types in comparison with the other three methods. When used hierarchically with all other typing systems, a further five types were found among isolates from two patients. However, some of the differences observed as a result of ribotyping could have been due to subtle changes produced by mutation, lysogenisation or gene transposition. Since the method requires additional time, expense and technical expertise, it is likely to be useful only when answers to specific epidemiological problems are required or as an initial screen before using other methods of genetic analysis.

Rapid characterisation of Candida albicans by pyrolysis mass spectrometry.

Clinical isolates (41) of Candida spp. from three possible outbreaks of nosocomially-acquired infection were compared by pyrolysis mass spectrometry (PMS) and by a combined morphotyping and resistotyping (M-R typing) method. Both systems characterised all the isolates and distinguished one isolate of C. tropicalis and another of C. glabrata from the 39 isolates of C. albicans. Results from both systems suggested that cross-infection with a single strain contributed to two of the outbreaks. In several instances, more than one strain of C. albicans was found amongst multiple isolates from the same patient. PMS is a simple, rapid and objective technique capable of characterising C. albicans isolates; discrimination was similar to M-R typing.

Pneumococci causing invasive disease in Britain 1982-1990.

A total of 5348 isolates of Streptococcus pneumoniae was serotyped and screened for insusceptibility to tetracycline, penicillin, erythromycin and chloramphenicol. Of these, 4238 (79%) were isolated from patients who had pneumonia or meningitis or were bacteraemic. Altogether, 3948 (74%) of the isolates belonged to one or other of the serotypes 1, 3, 4, 6, 8, 9, 14, 19 or 23 with serotypes 6, 14, 18, 19 and 23 being frequent causes of invasive disease in young children. Many isolates of type 1 were isolated from pneumonia and few from meningitis. Some 768 (14%) isolates were insusceptible to one or more antibiotic and 591 of these belonged to serotypes 6, 9, 14, 19 or 23. Representatives of type 14 resistant to erythromycin were prominent from 1986 onwards. There was an increase in the number of multi-resistant pneumococci from 1985. Among these were isolates of type 23 insusceptible to penicillin, chloramphenicol and tetracycline and cultures of type 6 resistant additionally to erythromycin.

Heterogeneous location of the mupA high-level mupirocin resistance gene in Staphylococcus aureus.

Epidemiologically unrelated clinical isolates of Staphylococcus aureus with high-level resistance to mupirocin (MIC > or = 512 mg/L) were studied to determine the location of the mupA resistance gene. The gene was carried on plasmids of variable size, some of which were transferable in vitro. DNA hybridisation of genomic DNA from 85 isolates showed that mupA was located on EcoRI fragments of seven different sizes; the most frequently observed fragments were 7 kb (46 isolates) or 4.1 kb (21 isolates). All isolates retained a 1.6-kb Nco I fragment that hybridised with mupA probes, but showed heterogeneous hybridisation patterns after digestion with Hinc II. These data suggested that mupA may be conserved, but that variation occurs in the flanking DNA proximal to it. Amplification of spacer regions between mupA and closest proximal copy of IS257 yielded products of variable size and was consistent with the presence of IS257 in either orientation. It is proposed that IS257-mediated events are responsible for the heterogeneity observed. The location of mupA varied between epidemiologically unrelated isolates of the same strain, including isolates of EMRSA-16 -- one of the two predominant methicillin-resistant strains in UK hospitals at the present time -- and this correlated with variations in the digestion patterns of the mupirocin resistance plasmids. The variable location of mupA should be evaluated further as a potential epidemiological tool with which to monitor the spread of high-level mupirocin resistance in EMRSA-16 or other strains of S. aureus.

Inter-centre comparison of pulsed-field gel electrophoresis for the typing of methicillin-resistant Staphylococcus aureus.

The results of pulsed-field gel electrophoresis (PFGE) of chromosomal DNA of the same 12 methicillin-resistant S. aureus (MRSA) strains of diverse geographical origin, performed in three different laboratories were compared; one laboratory used field-inversion gel electrophoresis (FIGE), one used contour clamped homogenous electrophoresis (CHEF) and one used both (all manufactured by BioRad Laboratories Inc., Hercules, CA, USA). No single method produced the maximum number of chromosomal fragments from all isolates. In only four instances were the same number of fragments identified by any two techniques. Although there were similar trends in strain identification the results showed many discrepancies even with a three-band difference rule to discriminate between strains. Plasmids in seven of the isolates produced a fragment, but this did not affect discrimination of the study isolates. There is a great need to standardise methodology and produce a standard set of strains to assist in this process.

Distribution of serovariants of group B streptococci in isolates from England and Norway.

The distribution of capsular polysaccharide antigen (CHO) types, surface-exposed c proteins alpha (c alpha) and beta (c beta) and an R-protein antigen was examined in 334 group B streptococci (GBS) isolates from three groups of patients hospitalised in England and Wales or Norway. The isolates were from 108 carriers, 67 cases of neonatal infection and 154 cases of adult infection. Each group contained all CHO types (Ia, Ib, II, III, IV, V and NT); type III strains predominated except in the adult infected group. Strains within each CHO type could be further subdivided by the protein markers into five subtypes by a combined typing system. The proportion of type Ib and type III strains in the neonatal infection cases and of type Ib strains in the adult infection cases significantly outnumbered isolates of these serotypes among the carrier strains. Twenty-nine different serovariants were identified; 24, 13 and 23 serovariants among the carrier, neonatal infection and adult infection isolates, respectively. Certain CHO antigen-protein associations were identified, notably those between Ia/c alpha, Ib/c alpha beta and III/R. The proportion of invasive isolates that expressed protein was not higher than in the carrier isolates. All CHO-type Ib isolates contained a c protein, but 7% of the Ib isolates did not contain any of these proteins. These findings indicate that this combined typing approach may be useful in examining epidemiological problems associated with GBS.

Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

OBJECTIVE: To review the evidence for the effectiveness of different isolation policies and screening practices in reducing the incidence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation and infection in hospital in-patients. To develop transmission models to study the effectiveness and cost-effectiveness of isolation policies in controlling MRSA. DATA SOURCES: MEDLINE, EMBASE, CINAHL, The Cochrane Library and SIGLE (1966-2000). Hand-searching key journals. No language restrictions. REVIEW METHODS: Key data were extracted from articles reporting MRSA-related outcomes and describing an isolation policy in a hospital with epidemic or endemic MRSA. No quality restrictions were imposed on studies using isolation wards (IW) or nurse cohorting (NC). Other studies were included if they were prospective or employed planned comparisons of retrospective data. Stochastic and deterministic models investigated long-term transmission dynamics, studying the effect of a fixed capacity IW, producing economic evaluations using local cost data. RESULTS: A total of 46 studies were accepted: 18 IWs, 9 NC, 19 other isolation policies. Most were interrupted time series, with few planned formal prospective studies. All but one reported multiple interventions. Consideration of potential confounders, measures to prevent bias, and appropriate statistical analysis were mostly lacking. No conclusions could be drawn in a third of studies. Most others provided evidence consistent with reduction of MRSA acquisition. Six long interrupted time series provided the strongest evidence. Four of these provided evidence that intensive control measures which included patient isolation were effective in controlling MRSA. In two others IW use failed to prevent endemic MRSA. There was no robust economic evaluation. Models showed that improving the detection rate or ensuring adequate isolation capacity reduced endemic levels, with substantial savings achievable. CONCLUSIONS: Major methodological weaknesses and inadequate reporting in published research mean that many plausible alternative explanations for reductions in MRSA acquisition associated with interventions cannot be excluded. No well-designed studies allow the role of isolation measures alone to be assessed. Nonetheless, there is evidence that concerted efforts that include isolation can reduce MRSA even when endemic. Little evidence was found to suggest that current isolation measures recommended in the UK are ineffective, and these should continue to be applied until further research establishes otherwise. The studies with the strongest evidence, together with the results of the modelling, provide testable hypotheses for future research. Guidelines to facilitate design of future research are produced.

Progress with establishing and implementing standards for infection control in the UK.

The process of agreeing standards for infection control in England and Wales is described. To ensure ownership of these standards an extensive consultation exercise was undertaken. Further development has been left to Infection Control Teams (ICTs) and the relevant health care workers. Management and Consultants in Communicable Disease Control were also sent the standards to further encourage support for their implementation. The results of a questionnaire of ICT resources and activities is alluded to and these data will be a valuable point of reference to monitor changes in the status quo of a rapidly changing health service.

Nosocomial antimicrobial resistance surveillance.

The global threat of antimicrobial resistance and potentially untreatable infections is a serious matter under review currently by the WHO and many countries throughout the world. I consider the optimal surveillance scheme and point out the various biases in the systems that we have been using in the UK over the last decade. MRSA are used as an example where similar trends have been identified in these systems and the information has, once again, proved to be of value to the MRSA control working party.

Do antimicrobials have a role in preventing septicaemia following instrumentation of the urinary tract?

Urinary tract instrumentation is a significant cause of septicaemia. Review of the literature suggests that selective use of antimicrobials would reduce the risk of septicaemia as this varies between patients and with procedures. Antimicrobial prophylaxis is indicated for patients at high risk of endocarditis, or who are neutropenic. For patients without these risk factors, it is indicated for open, transurethral, or certain forms of laser prostatectomy or trans-rectal prostate biopsy. For cystoscopy, antimicrobials are indicated for patients with preoperative bacteriuria or a preoperative indwelling catheter. Single dose aminoglycosides or oral fluoroquinolones are the agents of choice with the exception of the prevention of endocarditis, where combinations active against streptococci are recommended. For other instrumentations, the risk of antimicrobial toxicity probably outweighs the benefits and a risk-reduction strategy is recommended. Further studies are required to provide definitive answers in many of these areas.