The effect of ciprofloxacin prophylaxis during haematopoietic cell transplantation on infection episodes, exposure to treatment antimicrobials and antimicrobial resistance: a single-centre retrospective cohort study.

Objectives: Fluroquinolone prophylaxis during haematopoietic cell transplantation (HCT) remains contentious. We aimed to determine its effectiveness and association with exposure to treatment antimicrobials and antimicrobial resistance. Methods: All admission episodes for HCT (N = 400 , 372 unique patients) in a tertiary centre between January 2020 and December 2022 were studied. Allogeneic HCT (allo-HCT) recipients received prophylaxis with ciprofloxacin during chemotherapy-induced neutropenia, while autologous HCT (auto-HCT) recipients did not. Results: Allo-HCT was performed for 43.3% (173/400) of patients, auto-HCT for 56.7% (227/400). Allo-HCT was associated with an average of 1.01 fewer infection episodes per 100 admission days (95% CI 0.62-1.40, P < 0.001) compared with auto-HCT. In allo-HCT, the total exposure to all antimicrobials was higher [+24.8 days of therapy (DOT)/100 admission days, P < 0.001], as was exposure to ciprofloxacin (+40.5 DOT/100 admission days, P < 0.001). By contrast, exposure to meropenem (-4.5 DOT/100 admission days, P = 0.02), piperacillin/tazobactam (-5.2 DOT/100 admission days, P < 0.001), aminoglycosides (-4.5 DOT/100 admission days, P < 0.001) and glycopeptides (-6.4 DOT/100 admission days, P < 0.001) was reduced. Enterobacteriaceae isolated during allo-HCT were more resistant to ciprofloxacin (65.5%, 19/29 versus 6.1%, 2/33, P < 0001), ceftriaxone (65.5%, 19/29 versus 9.1%, 3/33, P < 0.001), other antimicrobial classes. Vancomycin-resistant enterococci were more common in allo-HCT recipients (11%, 19/173 versus 0.9%, 2/227, P < 0.001). Inpatient mortality during allo- and auto-HCT was 9.8% (17/173) and 0.4% (1/227). respectively (P < 0.001). Conclusions: Ciprofloxacin prophylaxis in allo-HCT was associated with fewer infection episodes and reduced exposure to treatment antimicrobials. Mortality in auto-HCT remained low. A significant burden of antimicrobial resistance was detected in allo-HCT recipients.

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.

The Impact of High-Frequency Chest-Wall Compression on Mechanical Ventilation Delivery and Flow Bias.

BACKGROUND: It is unclear if high-frequency chest-wall compression (HFCWC) has a role to assist with secretion clearance in patients on mechanical ventilation. The effect of HFCWC on the delivery of mechanical ventilation is unknown. This study describes the effect of HFCWC on mechanical ventilation delivery and flow bias in an orally intubated and mechanically ventilated bench model. METHODS: An orally intubated mannequin was mechanically ventilated in 5 commonly used modes of ventilation at settings that reflect current practice. HFCWC was applied via a randomized combination of oscillation frequencies and pressure settings. Mechanical ventilator flow, flow bias, and breathing frequency were measured before and during the application of HFCWC. RESULTS: HFCWC led to 3- to 7-fold increases in ventilator-delivered breathing frequency during synchronized intermittent mandatory ventilation, bi-level (with pressure support), bi-level-assist, and pressure-regulated volume control modes of ventilation. Only in the bi-level mode without pressure support was the ventilator breathing frequency unaffected by HFCWC. During HFCWC, peak inspiratory flow to peak expiratory flow ratios toward an expiratory flow bias, particularly at higher HFCWC pressures, only in pressure-regulated volume control and synchronized intermittent mandatory ventilation modes were peak inspiratory flow to peak expiratory flow ratios of <0.9 generated that would facilitate secretion clearance. CONCLUSIONS: HFCWC led to 3- to 7-fold increases in ventilator breathing frequency delivered by mechanical ventilation except in the bi-level mode. The bi-level mode may be the optimal mode to use HFCWC to minimize disruption to the delivered ventilator breathing frequency. The peak inspiratory flow to peak expiratory flow ratios < 0.9, the optimal flow bias for secretion clearance, was only achieved in the pressure-regulated volume control and synchronized intermittent mandatory ventilation modes. However, the findings in this bench model with a fixed low compliance may not be generalizable to the patient in the ICU, and we recommend further investigation into the effects of HFCWC in the patient in the ICU.

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia: Patient outcomes and impact of bendamustine dosing.

Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800-999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m2 had poorer PFS outcomes compared with those who received ≥600 mg/m2 (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.

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.

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.

Clinical and microbiologic features guiding treatment recommendations for brain abscesses in children.

BACKGROUND: There are no guidelines for the management of brain abscesses in children, and there is a paucity of recent data describing clinical and microbiologic features. We aimed to identify factors affecting outcome to inform antibiotic recommendations. METHODS: From 1999 to 2009, 118 children presented with brain abscesses to 4 neurosurgical centers in the United Kingdom. Clinical, microbiologic and treatment data were collected. RESULTS: The commonest preceding infection was sinusitis, with 59% of all children receiving antibiotics before diagnosis. Nonspecific symptoms were common, with only 13% having the triad of fever, headache and focal neurological deficit. Time between symptom onset and diagnosis varied widely (median, 10 days; range, 0-44). Magnetic resonance imaging was more frequently diagnostic than computed tomography. The most frequent organisms were Streptococcus milleri (38%), except after penetrating head injury or neurosurgery, for which Staphylococcus aureus was most common. The commonest empiric antibiotics were ceftriaxone/cefotaxime and metronidazole, which offered effective antimicrobial therapy in up to 83% of cases. Metronidazole added benefit in a maximum of 7% of cases, with ceftriaxone/cefotaxime alone sufficient in at least 76% and in all cases with cyanotic congenital heart disease or meningitis. A carbapenem would have been effective in 90%. The case fatality rate was 6% (33% in the immunocompromised). Long-term neurological sequelae affected 35%. Age younger than 5 years and a Glasgow Coma Scale score ≤8 were associated with poor outcome at 6 months. CONCLUSIONS: We recommend ceftriaxone/cefotaxime and metronidazole as empiric treatment, although metronidazole may be unnecessary in many cases, with antistaphylococcal cover in cases of head trauma. Meropenem potentially would be a better choice in the immunocompromised. A prospective study of intravenous and oral treatment guided by clinical improvement is required beause 1-2 weeks of intravenous antibiotics during a total of 6 weeks may be sufficient in children.