Presenting Symptoms in Newly Diagnosed Myeloma, Relation to Organ Damage, and Implications for Symptom-Directed Screening: A Secondary Analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) Trial.

Multiple myeloma (MM) patients risk diagnostic delays and irreversible organ damage. In those with newly diagnosed myeloma, we explored the presenting symptoms to identify early signals of MM and their relationships to organ damage. The symptoms were recorded in patients' own words at diagnosis and included diagnostic time intervals. Those seen by a haematologist >6 months prior to MM diagnosis were classified as precursor disease (PD). Most (962/977) patients provided data. Back pain (38%), other pain (31%) and systemic symptoms (28%) predominated. Patients rarely complain of 'bone pain', simply 'pain'. Vertebral fractures are under-recognised as pathological and are the predominant irreversible organ damage (27% of patients), impacting the performance status (PS) and associated with back pain (odds ratio (OR) 6.14 [CI 4.47-8.44]), bone disease (OR 3.71 [CI 1.88-7.32]) and age >65 years (OR 1.58 [CI 1.15-2.17]). Renal failure is less frequent and associated with gastrointestinal symptoms (OR 2.23 [CI1.28-3.91]), age >65 years (OR 2.14 [CI1.28-3.91]) and absence of back pain (OR 0.44 [CI 0.29-0.67]). Patients with known PD (n = 149) had fewer vertebral fractures (p = 0.001), fewer adverse features (p = 0.001), less decline in PS (p = 0.001) and a lower stage (p = 0.04) than 813 with de novo MM. Our data suggest subgroups suitable for trials of 'symptom-directed' screening: those with back pain, unexplained pain, a general decline in health or low-impact vertebral compression fractures.

The QuantuMDx Q-POC SARS-CoV-2 RT-PCR assay for rapid detection of COVID-19 at point-of-care: preliminary evaluation of a novel technology.

Accurate and rapid point-of-care (PoC) diagnostics are critical to the control of the COVID-19 pandemic. The current standard for accurate diagnosis of SARS-CoV-2 is laboratory-based reverse transcription polymerase chain reaction (RT-PCR) assays. Here, a preliminary prospective performance evaluation of the QuantuMDx Q-POC SARS-CoV-2 RT-PCR assay is reported. Between November 2020 and March 2021, 49 longitudinal combined nose/throat (NT) swabs from 29 individuals hospitalised with RT-PCR confirmed COVID-19 were obtained at St George's Hospital, London. In addition, 101 mid-nasal (MN) swabs were obtained from healthy volunteers in June 2021. These samples were used to evaluate the Q-POC SARS-CoV-2 RT-PCR assay. The primary analysis was to compare the sensitivity and specificity of the Q-POC test against a reference laboratory-based RT-PCR assay. The overall sensitivity of the Q-POC test compared with the reference test was 96.88% (83.78- 99.92% CI) for a cycle threshold (Ct) cut-off value for the reference test of 35 and 80.00% (64.35-90.95% CI) without altering the reference test's Ct cut-off value of 40. The Q-POC test is a sensitive, specific and rapid PoC test for SARS-CoV-2 at a reference Ct cut-off value of 35. The Q-POC test provides an accurate option for RT-PCR at PoC without the need for sample pre-processing and laboratory handling, enabling rapid diagnosis and clinical triage in acute care and other settings.

SARS-CoV-2 enzyme-linked immunosorbent assays as proxies for plaque reduction neutralisation tests.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread globally since its emergence in 2019. Most SARS-CoV-2 infections generate immune responses leading to rising levels of immunoglobulins (Ig) M, A and G which can be detected using diagnostic tests including enzyme-linked immunosorbent assays (ELISA). Whilst implying previous SARS-CoV-2 infection, the detection of Ig by ELISA does not guarantee the presence of neutralising antibodies (NAb) that can prevent the virus infecting cells. Plaque reduction neutralisation tests (PRNT) detect NAb, but are not amenable to mass testing as they take several days and require use of SARS-CoV-2 in high biocontainment laboratories. We evaluated the ability of IgG and IgM ELISAs targeting SARS-CoV-2 spike subunit 1 receptor binding domain (S1-RBD), and spike subunit 2 (S2) and nucleocapsid protein (NP), at predicting the presence and magnitude of NAb determined by PRNT. IgG S2 + NP ELISA was 96.8% [95% CI 83.8-99.9] sensitive and 88.9% [95% CI 51.8-99.7] specific at predicting the presence of NAbs (PRNT80 > 1:40). IgG and IgM S1-RBD ELISAs correlated with PRNT titre, with higher ELISA results increasing the likelihood of a robust neutralising response. The IgM S1-RBD assay can be used as a rapid, high throughput test to approximate the magnitude of NAb titre.

Production and use of encapsidated RNA mimics as positive control reagents for SARS-CoV-2 RT-qPCR diagnostics.

The current gold standard technique for SARS-CoV-2 diagnostics is hydrolysis probe-based RT-qPCR. Reliable testing requires reliable control reagents to monitor the efficiency of RNA extraction, reverse transcription and PCR amplification. Here we describe a custom RNA packaging system from the plant virus cowpea mosaic virus to produce virus-like particles that encapsidate specifically designed portions of the genome of SARS-CoV-2, the causative agent of COVID-19. These encapsidated mimics are highly stable particles which can be used either to spike patient swab samples for use as an in-tube extraction and reaction positive control in multiplex RT-qPCR, or alone as a side-by-side mock-positive control reagent. The selection of sequences in the packaged pseudogenomes ensures that these mimics are compatible with the most commonly used primer/probe combinations for SARS-CoV-2 diagnostics (including German Berlin Charité Hospital, American CDC, and Chinese CDC protocols). The plant transient expression system used to produce these encapsidated mimics is inherently low-cost, and sufficiently high-yielding that a single laboratory-scale preparation can provide enough positive control reagent for millions of tests.

Twelve lateral flow immunoassays (LFAs) to detect SARS-CoV-2 antibodies.

BACKGROUND: There are an abundance of commercially available lateral flow assays (LFAs) that detect antibodies to SARS-CoV-2. Whilst these are usually evaluated by the manufacturer, externally performed diagnostic accuracy studies to assess performance are essential. Herein we present an evaluation of 12 LFAs. METHODS: Sera from 100 SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) positive participants were recruited through the FASTER study. A total of 105 pre-pandemic sera from participants with other infections were included as negative samples. RESULTS: At presentation sensitivity against RT-PCR ranged from 37.4 to 79% for IgM/IgG, 30.3-74% for IgG, and 21.2-67% for IgM. Sensitivity for IgM/IgG improved ≥ 21 days post symptom onset for 10/12 tests. Specificity ranged from 74.3 to 99.1% for IgM/IgG, 82.9-100% for IgG, and 75.2-98% for IgM. Compared to the EuroImmun IgG enzyme-linked immunosorbent assay (ELISA), sensitivity and specificity ranged from 44.6 to 95.4% and 85.4-100%, respectively. CONCLUSION: There are many LFAs available with varied sensitivity and specificity. Understanding the diagnostic accuracy of these tests will be vital as we come to rely more on the antibody status of a person moving forward, and as such manufacturer-independent evaluations are crucial.

Antibiotic Susceptibility, Virulome, and Clinical Outcomes in European Infants with Bloodstream Infections Caused by Enterobacterales.

Mortality in neonates with Gram-negative bloodstream infections has remained unacceptably high. Very few data are available on the impact of resistance profiles, virulence factors, appropriateness of empirical treatment and clinical characteristics on patients' mortality. A survival analysis to investigate 28-day mortality probability and predictors was performed including (I) infants <90 days (II) with an available Enterobacterales blood isolate with (III) clinical, treatment and 28-day outcome data. Eighty-seven patients were included. Overall, 299 virulence genes were identified among all the pathogens. Escherichia coli had significantly more virulence genes identified compared with other species. A strong positive correlation between the number of resistance and virulence genes carried by each isolate was found. The cumulative probability of death obtained by the Kaplan-Meier survival analysis was 19.5%. In the descriptive analysis, early age at onset, gestational age at onset, culture positive for E. coli and number of classes of virulence genes carried by each isolate were significantly associated with mortality. By Cox multivariate regression, none of the investigated variables was significant. This pilot study has demonstrated the feasibility of investigating the association between neonatal sepsis mortality and the causative Enterobacterales isolates virulome. This relationship needs further exploration in larger studies, ideally including host immunopathological response, in order to develop a tailor-made therapeutic strategy.

Self-sampling of capillary blood for SARS-CoV-2 serology.

Serological testing is emerging as a powerful tool to progress our understanding of COVID-19 exposure, transmission and immune response. Large-scale testing is limited by the need for in-person blood collection by staff trained in venepuncture, and the limited sensitivity of lateral flow tests. Capillary blood self-sampling and postage to laboratories for analysis could provide a reliable alternative. Two-hundred and nine matched venous and capillary blood samples were obtained from thirty nine participants and analysed using a COVID-19 IgG ELISA to detect antibodies against SARS-CoV-2. Thirty eight out of thirty nine participants were able to self-collect an adequate sample of capillary blood (≥ 50 µl). Using plasma from venous blood collected in lithium heparin as the reference standard, matched capillary blood samples, collected in lithium heparin-treated tubes and on filter paper as dried blood spots, achieved a Cohen's kappa coefficient of > 0.88 (near-perfect agreement, 95% CI 0.738-1.000). Storage of capillary blood at room temperature for up to 7 days post sampling did not affect concordance. Our results indicate that capillary blood self-sampling is a reliable and feasible alternative to venepuncture for serological assessment in COVID-19.

Human papillomavirus (HPV) vaccination and oropharyngeal HPV in ethnically diverse, sexually active adolescents: community-based cross-sectional study.

OBJECTIVES: Oropharyngeal squamous cell carcinoma is the most common human papillomavirus (HPV)-associated cancer in the UK, but little is known about the prevalence of oropharyngeal HPV in sexually active teenagers. We investigated reported HPV vaccination coverage (in females) and prevalence of oropharyngeal HPV in sexually active students attending six technical colleges in London, UK. METHODS: In 2017, we obtained mouthwash samples and questionnaires from male and female students taking part in the 'Test n Treat' chlamydia screening trial. Samples were subjected to HPV genotyping. RESULTS: Of 232 participants approached, 202 (87%) provided a mouthwash sample and questionnaire. Participants' median age was 17 years and 47% were male. Most (73%) were from black and minority ethnic groups, 64% gave a history of oral sex, 52% reported having a new sexual partner in the past 6 months, 33% smoked cigarettes, 5.9% had concurrent genitourinary Chlamydia trachomatis infection and 1.5% Neisseria gonorrhoeae and 5.0% were gay or bisexual. Only 47% (50/107) of females reported being vaccinated against HPV 16/18, of whom 74% had received ≥2 injections. HPV genotyping showed three mouthwash samples (1.5%, 95% CI 0.3% to 4.3%) were positive for possible high-risk human papillomavirus (HR-HPV), one (0.5%, 0.0% to 2.7%) for low-risk HPV 6/11, but none (0.0%, 0.0% to 1.8%) for HR-HPV. Four samples (2.0%, 0.5% to 5.0%) were positive for HPV16 using a HPV16 type-specific quantitative PCR, but these were at a very low copy number and considered essentially negative. CONCLUSIONS: Despite the high prevalence of oral sex and genitourinary chlamydia and low prevalence of HPV vaccination, the prevalence of oropharyngeal HR-HPV in these adolescents was negligible.

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression.

IgG Seroconversion and Pathophysiology in Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Treatment and Outcomes of Children With Febrile Urinary Tract Infection Due to Extended Spectrum Beta-lactamase-producing Bacteria in Europe: TOO CUTE Study.

BACKGROUND: The prevalence of extended-spectrum beta-lactamase producing Εnterobacteriaceae (ESBL-PE) is increasing globally. ESBL-PE are an important cause of urinary tract infections (UTIs) in children. We aimed to characterize the clinical presentation, treatment and outcomes of childhood UTI caused by ESBL-PE in Europe. METHODS: Multicenter retrospective cohort study. Children 0 to 18 years of age with fever, positive urinalysis and positive urine culture for an ESBL-PE uropathogen, seen in a participating hospital from January 2016 to July 2017, were included. MAIN OUTCOME MEASURES: Primary outcome measure: day of defervescence was compared between (1) initial microbiologically effective treatment (IET) versus initial microbiologically ineffective treatment (IIT) and (2) single initial antibiotic treatment versus combined initial antibiotic treatment. SECONDARY OUTCOME MEASURES: Clinical and microbiologic failure of initial treatment. RESULTS: We included 142 children from 14 hospitals in 8 countries. Sixty-one children had IET and 77 IIT. There was no statistical difference in time to defervescence for effective/ineffective groups (P = 0.722) and single/combination therapy groups (P = 0.574). Two of 59 (3.4%) and 4/66 (6.1%) patients exhibited clinical failure during treatment (P = 0.683) when receiving IET or IIT, respectively. Eight of 51 (15.7%) receiving IET and 6/58 (10.3%) receiving IIT patients (P = 0.568) had recurring symptoms/signs suggestive of a UTI. Recurrence of a UTI occurred 15.5 days (interquartile range, 9.0-19.0) after the end of treatment. CONCLUSIONS: Time to defervescence and clinical failure did not differ between IET/IIT groups. Non-carbapenem beta-lactam antibiotics may be used for the empiric treatment of ESBL febrile UTIs, until susceptibility testing results become available.

Multicentre study of the in vitro activity of ceftolozane/tazobactam and other commonly used antibiotics against Pseudomonas aeruginosa isolates from patients in the UK.

OBJECTIVES: To evaluate the in vitro activity of ceftolozane/tazobactam and other commonly used antipseudomonal antibiotics against geographically spread Pseudomonas aeruginosa isolates in the UK using disc susceptibility testing. METHODS: The in vitro activity of ceftolozane/tazobactam and nine other commonly used antipseudomonal antibiotics was evaluated. Isolates were collected between January 2015 and April 2018. Susceptibility results were interpreted using EUCAST 2018 criteria. RESULTS: Overall, 1326 clinical isolates from 14 centres in the UK were tested. The majority of the isolates were collected from non-cystic fibrosis (non-CF) patients (n = 1123, 85.0%). In addition, 199 cystic fibrosis (CF) isolates were collected from 10 centres. Overall susceptibility to ceftolozane/tazobactam was 89.3% (n = 1181), which included 128 CF and 1053 non-CF isolates. The other antibacterial agents with the highest susceptibility were tobramycin (92.4%, n = 1221) and piperacillin/tazobactam (90.7%, n = 1199). Susceptibility to all antibacterial agents was lower for CF isolates. Piperacillin/tazobactam was the most active of the antibacterial agents tested, followed by ceftolozane/tazobactam (70.4% and 64.3%, respectively), and <60% of CF isolates were susceptible to ceftazidime and the carbapenems. The reason for the higher rates of susceptibility to piperacillin/tazobactam and lower susceptibility to ceftazidime compared with other studies is unclear. CONCLUSIONS: The data presented here support the need to investigate the place of ceftolozane/tazobactam as a treatment option in the management of pseudomonal infections, particularly in patients with CF. The results highlight the importance of routine testing of new antibacterial agents and of making the data available to clinicians to make appropriate and informed treatment choices.

Developing a serocorrelate of protection against invasive group B streptococcus disease in pregnant women: a feasibility study.

BACKGROUND: Group B streptococcus is the leading cause of infection in infants. Currently, intrapartum antibiotic prophylaxis is the major strategy to prevent invasive group B streptococcus disease. However, intrapartum antibiotic prophylaxis does not prevent maternal sepsis, premature births, stillbirths or late-onset disease. Maternal vaccination may offer an alternative strategy. Multivalent polysaccharide protein conjugate vaccine development is under way and a serocorrelate of protection is needed to expedite vaccine licensure. OBJECTIVES: The ultimate aim of this work is to determine the correlate of protection against the major group B streptococcus disease-causing serotypes in infants in the UK. The aim of this feasibility study is to test key operational aspects of the study design. DESIGN: Prospective cohort study of pregnant women and their infants in a 6-month period (1 July to 31 December 2018). SETTING: Five secondary and tertiary hospitals from London and South England. National iGBS disease surveillance was conducted in all trusts in England and Wales. PARTICIPANTS: Pregnant women aged ≥ 18 years who were delivering at one of the selected hospitals and who provided consent during the study period. There were no exclusion criteria. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: (1) To test the feasibility of collecting serum at delivery from a large cohort of pregnant women. (2) To test the key operational aspects for a proposed large serocorrelates study. (3) To test the feasibility of collecting samples from those with invasive group B streptococcus. RESULTS: A total of 1823 women were recruited during the study period. Overall, 85% of serum samples were collected at three sites collecting only cord blood. At the two sites collecting maternal, cord and infant blood samples, the collection rate was 60%. A total of 614 women were screened for group B streptococcus with a colonisation rate of 22% (serotype distribution: 30% III, 25% Ia, 16% II, 14% Ib, 14% V and 1% IV). A blood sample was collected from 34 infants who were born to colonised women. Maternal and infant blood and the bacterial isolates for 15 newborns who developed invasive group B streptococcal disease during the study period were collected (serotype distribution: 29% III, 29% II, 21% Ia, 7% Ib, 7% IV and 7% V). LIMITATIONS: Recruitment and sample collection were dependent on the presence of research midwives rather than the whole clinical team. In addition, individualised consent limited the number of women who could be approached each day, and site set-up for the national surveillance study and the limited time period of this feasibility study limited recruitment of all eligible participants. CONCLUSIONS: We have verified the feasibility of collecting and processing rectovaginal swabs and blood samples in pregnant women, as well as samples from those with invasive group B streptococcal disease. We have made recommendations for the recruitment of cases within the proposed GBS3 study and for controls both within GBS3 and as an extension of this feasibility study. FUTURE WORK: A large case-control study comparing specific immunoglobulin G levels in mothers whose infants develop invasive group B streptococcal disease with those in colonised mothers whose infants do not develop invasive group B streptococcal disease is recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49326091; IRAS project identification number 246149/REC reference number 18/WM/0147. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 67. See the NIHR Journals Library website for further project information.

Group B streptococcus is often carried by healthy women and usually causes no problems. Group B streptococcus may be passed from mother to child, primarily through the birth canal, and, in rare cases, can cause serious disease (i.e. pneumonia, sepsis or meningitis) and even death in babies. It may be possible to prevent group B streptococcus disease in babies by giving a vaccine to pregnant women. The reason for vaccinating the mother is so that she can pass on protection (antibodies) during the pregnancy to her baby. A vaccine is currently being developed against group B streptococcus that aims to boost this protection. To help vaccine development progress faster, we need to find out how much antibody is actually needed to protect babies from group B streptococcus disease. A large study is needed to address this question; therefore, we have performed a feasibility study to assess the practicalities of performing this large study. Specifically, we will assess (1) women's willingness to participate in a swabbing and cord blood study, (2) the ability to collect swabs and cord blood once recruited, (3) the ability to identify group B streptococcus disease in this population and (4) the laboratory processing of samples. We recruited 1823 pregnant women from five maternity units in England in a 6-month period: 22% of all women delivering at all sites and 74% of those women who were approached. In three hospitals, cord blood samples from 85% of 1201 women were collected. In two hospitals, we collected 60% of maternal blood samples, 53% of cord blood samples and 99% of swabs from the vagina and rectum from 622 women. A total of 22% of these women carried group B streptococcus in their vagina or gut and we collected blood samples from 34 healthy babies born to these women. During the study, we collected samples from 15 babies who had developed severe group B streptococcus disease; four babies were born to women participating in the study and the rest were identified through national surveillance. In conclusion, we have verified the feasibility of collecting and processing swabs from the vagina and rectum and blood samples in pregnant women, as well as samples from babies who developed group B streptococcus disease. In addition, we have identified a number of strategies that could be adopted in a future study in order to increase recruitment and sample collection.

Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.

BACKGROUND: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile. There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial. OBJECTIVES: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio. SETTING: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales. PARTICIPANTS: A total of 977 patients with newly diagnosed symptomatic myeloma. INTERVENTION: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year. MAIN OUTCOME MEASURES: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond. RESULTS: In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival (p = 0.94). LIMITATIONS: Short duration of prophylactic antibiotics and cost-effectiveness. CONCLUSIONS: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04). TRIAL REGISTRATION: Current Controlled Trials ISRCTN51731976. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Myeloma is a type of cancer that develops from cells in the bone marrow, called plasma cells, which are part of the immune system. Because myeloma affects the immune system, people who have it are at greater risk of picking up infections. This risk is higher at the start of antimyeloma therapy when the myeloma is active. WHAT DID THE STUDY DO?: The trial looked to see if the risk of getting an infection can be reduced, rather than waiting to see if an infection developed and then treating it. An antibiotic already used all over the world, called levofloxacin was tested. Half of the patients (n = 489) took levofloxacin for 12 weeks and the other half (n = 488) were given a dummy tablet (placebo). The aim was to see if taking levofloxacin at the start of antimyeloma therapy reduced the risk of getting an infection. Alongside this, we evaluated three important groups of antibiotic-resistant bacteria to see whether or not the use of preventative levofloxacin increased the number of these resistant bacteria living in the body. In addition, the overall survival, economic impacts and the impact of using preventative antibiotics on patients' quality of life and response to antimyeloma treatment were evaluated. WHAT DID THE STUDY FIND?: During the 12 weeks from new diagnosis of myeloma, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced the number of febrile episodes and deaths [134 (febrile episodes alone, n = 112; febrile episodes plus death, n = 7; deaths alone, n = 15) out of 488 (27%) placebo patients vs. 95 (febrile episodes alone, n = 87; febrile episodes plus death, n = 4; deaths alone, n = 4) out of 489 (19%) levofloxacin patients; p = 0.002] without increasing antibiotic-resistant bacteria.

Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma. METHODS: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35. FINDINGS: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group. INTERPRETATION: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy. FUNDING: UK National Institute for Health Research.

The predictive value of quantitative nucleic acid amplification detection of Clostridium difficile toxin gene for faecal sample toxin status and patient outcome.

BACKGROUND: Laboratory diagnosis of Clostridium difficile infection (CDI) remains unsettled, despite updated guidelines. We investigated the potential utility of quantitative data from a nucleic acid amplification test (NAAT) for C. difficile toxin gene (tg) for patient management. METHODS: Using data from the largest ever C. difficile diagnostic study (8853 diarrhoeal samples from 7335 patients), we determined the predicative value of C. difficile tgNAAT (Cepheid Xpert C.diff) low cycle threshold (CT) value for patient toxin positive status, CDI severity, mortality and CDI recurrence. Reference methods for CDI diagnosis were cytotoxicity assay (CTA) and cytotoxigenic culture (CTC). RESULTS: Of 1281 tgNAAT positive faecal samples, 713 and 917 were CTA and CTC positive, respectively. The median tgNAAT CT for patients who died was 25.5 vs 27.5 for survivors (p = 0.021); for toxin-positivity was 24.9 vs 31.6 for toxin-negative samples (p<0.001) and for patients with a recurrence episode was 25.6 vs 27.3 for those who did not have a recurrent episode (p = 0.111). Following optimal cut-off determination, low CT was defined as ≤25 and was significantly associated with a toxin-positive result (P<0.001, positive predictive value 83.9%), presence of PCR-ribotype 027 (P = 0.025), and mortality (P = 0.032). Recurrence was not associated with low CT (p 0.111). CONCLUSIONS: Low tgNAAT CT could indicate CTA positive patients, have more severe infection, increased risk of mortality and possibly recurrence. Although, the limited specificity of tgNAAT means it cannot be used as a standalone test, it could augment a more timely diagnosis, and optimise management of these at-risk patients.

Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies.

Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking. Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS). Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed. Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome. Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.