Impact of antibiotic timing on mortality from Gram-negative bacteraemia in an English district general hospital: the importance of getting it right every time.

OBJECTIVES: There is limited evidence that empirical antimicrobials affect patient-oriented outcomes in Gram-negative bacteraemia. We aimed to establish the impact of effective antibiotics at four consecutive timepoints on 30 day all-cause mortality and length of stay in hospital. METHODS: We performed a multivariable survival analysis on 789 patients with Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa bacteraemias. Antibiotic choices at the time of the blood culture (BC), the time of medical clerking and 24 and 48 h post-BC were reviewed. RESULTS: Patients that received ineffective empirical antibiotics at the time of the BC had higher risk of mortality before 30 days (HR = 1.68, 95% CI = 1.19-2.38, P = 0.004). Mortality was higher if an ineffective antimicrobial was continued by the clerking doctor (HR = 2.73, 95% CI = 1.58-4.73, P < 0.001) or at 24 h from the BC (HR = 1.83, 95% CI = 1.05-3.20, P = 0.033) when compared with patients who received effective therapy throughout. Hospital-onset infections, 'high inoculum' infections and elevated C-reactive protein, lactate and Charlson comorbidity index were independent predictors of mortality. Effective initial antibiotics did not statistically significantly reduce length of stay in hospital (-2.98 days, 95% CI = -6.08-0.11, P = 0.058). The primary reasons for incorrect treatment were in vitro antimicrobial resistance (48.6%), initial misdiagnosis of infection source (22.7%) and non-adherence to hospital guidelines (15.7%). CONCLUSIONS: Consecutive prescribing decisions affect mortality from Gram-negative bacteraemia.

Exploring the views of infection consultants in England on a novel delinked funding model for antimicrobials: the SMASH study.

Objectives: A novel 'subscription-type' funding model was launched in England in July 2022 for ceftazidime/avibactam and cefiderocol. We explored the views of infection consultants on important aspects of the delinked antimicrobial funding model. Methods: An online survey was sent to all infection consultants in NHS acute hospitals in England. Results: The response rate was 31.2% (235/753). Most consultants agreed the model is a welcome development (69.8%, 164/235), will improve treatment of drug-resistant infections (68.5%, 161/235) and will stimulate research and development of new antimicrobials (57.9%, 136/235). Consultants disagreed that the model would lead to reduced carbapenem use and reported increased use of cefiderocol post-implementation. The presence of an antimicrobial pharmacy team, requirement for preauthorization by infection specialists, antimicrobial stewardship ward rounds and education of infection specialists were considered the most effective antimicrobial stewardship interventions. Under the new model, 42.1% (99/235) of consultants would use these antimicrobials empirically, if risk factors for antimicrobial resistance were present (previous infection, colonization, treatment failure with carbapenems, ward outbreak, recent admission to a high-prevalence setting).Significantly higher insurance and diversity values were given to model antimicrobials compared with established treatments for carbapenem-resistant infections, while meropenem recorded the highest enablement value. Use of both 'subscription-type' model drugs for a wide range of infection sites was reported. Respondents prioritized ceftazidime/avibactam for infections by bacteria producing OXA-48 and KPC and cefiderocol for those producing MBLs and infections with Stenotrophomonas maltophilia, Acinetobacter spp. and Burkholderia cepacia. Conclusions: The 'subscription-type' model was viewed favourably by infection consultants in England.

Long-term outcome and risk factors for late mortality in Gram-negative bacteraemia: a retrospective cohort study.

OBJECTIVES: The long-term outcomes of patients following Gram-negative bacteraemia (GNB) are poorly understood. Here we describe a cohort of patients with GNB over a 2-year period and determine factors associated with late mortality (death between Days 31 and 365 after detection of bacteraemia). METHODS: This was a single-centre, retrospective, observational cohort study of 789 patients with confirmed Escherichia coli, Klebsiella spp. or Pseudomonas aeruginosa bacteraemia with a follow-up of 1 year. Multivariable survival analysis was used to determine risk factors for late mortality in patients who survived the initial 30-day period of infection. RESULTS: Overall, 1-year all-cause mortality was 36.2%, with 18.1% of patients dying within 30 days and 18.1% of patients suffering late mortality. An adverse antimicrobial resistance profile [hazard ratio (HR) = 1.095 per any additional antimicrobial category, 95% confidence interval (CI) 1.018-1.178; P = 0.014] and infection with P. aeruginosa (HR = 2.08, 95% CI 1.11-3.88; P = 0.022) were independent predictors of late mortality. Other significant factors included Charlson comorbidity index and length of hospitalisation after the index blood culture. CONCLUSION: Patients with GNB have a poor long-term prognosis. Risk factors for greater mortality at 1 year include co-morbidity, length of hospitalisation, and infecting organism and its resistance profile.

Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children.

BACKGROUND: Oseltamivir, a specific influenza neuraminidase inhibitor, is an effective treatment for seasonal influenza. Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different from that used throughout the rest of the world. We investigated the emergence of drug-resistant infection in children treated with a tiered weight-based dosing regimen. METHODS: We analyzed sequential clinical nasopharyngeal samples, obtained before and after tiered weight-based oseltamivir therapy, from children with acute influenza during 2005-2007. We isolated viruses, tested for drug resistance with use of a fluorescence-based neuraminidase inhibition assay, performed neuraminidase gene sequencing, and determined quantitative viral loads. RESULTS: Sixty-four children (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, and 19 with influenza B virus) aged 1-12 years (median age, 3 years, 1 month) were enrolled. By days 4-7 after initiation of treatment, of 64 samples tested, 47 (73.4%) and 26 (40.6%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. By days 8-12 after initiation of treatment, of 53 samples tested, 18 (33.9%) and 1 (1.8%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. We found no statistically significant differences in the reduction of viral shedding or time to clearance of virus between viral subtypes. Antiviral-resistant viruses were recovered from 3 (27.3%) of 11 children with influenza A subtype H1N1, 1 (2.9%) of 34 children with influenza A subtype H3N2, and 0 (0%) of 19 children with influenza B virus, all of whom were treated with oseltamivir (P = .004). There was no evidence of prolonged illness in children infected with drug-resistant virus. CONCLUSIONS: Drug resistance emerges at a higher rate in influenza A subtype H1N1 virus than in influenza A subtype H3N2 or influenza B virus after tiered weight-based oseltamivir therapy. Virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles.

Rapid quantitation of neuraminidase inhibitor drug resistance in influenza virus quasispecies.

BACKGROUND: Emerging resistance of influenza viruses to neuraminidase inhibitors is a concern, both in surveillance of global circulating strains and in treatment of individual patients. Current methodologies to detect resistance rely on the use of cultured virus, thus taking time to complete or lacking the sensitivity to detect mutations in viral quasispecies. Methodology for rapid detection of clinically meaningful resistance is needed to assist individual patient management and to track the transmission of resistant viruses in the community. METHODS: We have developed a pyrosequencing methodology to detect and quantitate influenza neuraminidase inhibitor resistance mutations in cultured virus and directly in clinical material. Our assays target polymorphisms associated with drug resistance in the neuraminidase genes of human influenza A H1N1 as well as human and avian H5N1 viruses. Quantitation can be achieved using viral RNA extracted directly from respiratory or tissue samples, thus eliminating the need for virus culture and allowing the assay of highly pathogenic viruses such as H5N1 without high containment laboratory facilities. RESULTS: Antiviral-resistant quasispecies are detected and quantitated accurately when present in the total virus population at levels as low as 10%. Pyrosequencing is a real-time assay; therefore, results can be obtained within a clinically relevant timeframe and provide information capable of informing individual patient or outbreak management. CONCLUSIONS: Pyrosequencing is ideally suited for early identification of emerging antiviral resistance in human and avian influenza infection and is a useful tool for laboratory surveillance and pandemic preparedness.

The potential impact of neuraminidase inhibitor resistant influenza.

PURPOSE OF REVIEW: Neuraminidase inhibitor resistant influenza virus has recently emerged, and circulated, in untreated persons. Influenza virus evolution is causing antiviral susceptibility to change. We review the latest research in this rapidly moving field. RECENT FINDINGS: Oseltamivir-resistant influenza H1N1 emerged globally, without drug selection pressure, during the 2007-2008 northern hemisphere influenza season. This unexpected event, coupled with reports of reducing susceptibilities of influenza B and H5N1, contradicts our understanding of the properties of neuraminidase inhibitor resistant influenza viruses. Knowledge of the structure of the neuraminidases and impact of mutations on drug binding has now expanded. Surveillance and clinical studies have identified key areas which require focused research such as the incidence of resistance in children and immunocompromised populations and the need for improved methodologies for detecting resistant virus on an individual and population level. SUMMARY: Neuraminidase inhibitors, oseltamivir in particular, are the drugs of choice against seasonal influenza, zoonotic H5N1 and are stockpiled as the primary mitigating strategy for pandemic influenza containment and control. Further clinical and animal studies are essential to fully understand the capacity of neuraminidase inhibitor resistant influenza to be tolerated in the virus population, whilst retaining virulence and transmissibility. Vigilance, policy review and development of new anti-influenza drugs are essential.

Risky behaviour: a rare complication of an uncommon disease in a returning traveller.

A 49-year-old man with a history of hypertension and no known drug allergies was admitted with a 4-day history of fever, general malaise, sore throat and diarrhoea. Eleven days ago, he had returned from a 2-week adventure holiday to South Africa. On admission, he was noted to have a creatinine 392 µmol/L, alanine aminotransferase 133 IU/L, alkaline phosphatase 211 IU/L and platelets 151×10(9)/L. A differential diagnosis of suspected leptospirosis or bacterial sepsis was made and he was started on ceftriaxone. Two hours later he became hypotensive, tachypnoeic with severe myalgia and a temperature of 41°C, type I respiratory failure and metabolic acidosis. There was no stridor, facial swelling or rash. A diagnosis of Jarisch-Herxheimer reaction was made. A second dose of ceftriaxone was given without any reaction. The patient thereafter completed 7 days of doxycycline. PCR confirmed leptospirosis and subsequent leptospirosis IgM was positive. He improved clinically with treatment and was discharged after 10 days of admission.

Use of neuraminidase inhibitors to combat pandemic influenza.

Since the last influenza pandemic in 1968, neuraminidase (NA) inhibitors have been licensed for the treatment and prophylaxis of seasonal influenza. Continuing outbreaks of highly pathogenic avian influenza H5N1 since 2004 have focused attention on the timing of the next pandemic and preparedness plans. Although immunization is the principal means of influenza prophylaxis, a well-matched efficacious vaccine is unlikely to be widely available for several months following the emergence of the pandemic strain. NA inhibitors could be used to contain and eliminate an emerging pandemic virus at source. If unsuccessful, they could still play a crucial role in reducing the medical impact of pandemic influenza as it spreads through countries. Accordingly, many authorities are creating stockpiles of NA inhibitors. However, the use of stockpiled drugs for treatment or prophylaxis, the rapid delivery to newly diagnosed cases and unknown characteristics of an emergent pandemic strain pose significant challenges to determining optimal use of stockpiles.

Influenza: current threat from avian influenza.

Influenza is an infectious respiratory pathogen causing annual outbreaks and infrequent pandemics, resulting in significant morbidity, mortality and burdens on the delivery of health care. The geographical spread of highly pathogenic avian influenza (HPAI) H5N1 among poultry and wild bird populations is unprecedented. Growing numbers of sporadic avian influenza infections are occurring in humans, increasing the threat of the next influenza pandemic. Vaccines are the principle means of combating influenza, and a number of studies with H5N1 vaccine candidates are underway. Antiviral agents can be used to treat influenza infection and can be taken as chemoprophylaxis during influenza outbreaks. Oseltamivir has been stockpiled as part of influenza pandemic preparedness planning; however, the emergence of drug resistance may limit its clinical use.