Implementation of a clinical decision rule for selecting empiric treatment for invasive aspergillosis in a setting with high triazole resistance.

World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance. LAY SUMMARY: Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.

Study protocol: effect of infection, Modic and inflammation on clinical outcomes in surgery for radiculopathy (EIMICOR).

BACKGROUND: Evidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology (Modic changes; MC) is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the (possibly bacterial induced) inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery. METHODS: This prospective cohort study will include 160 lumbar and 160 cervical patients (total of 320), which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection (blood sample evaluation) will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck (cervical spine) Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks. DISCUSSION: Gaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery. TRIAL REGISTRATION: prospectively enrolled at trialregister.nl, ID: NL8464 .

Intravesical Gentamicin Treatment for Recurrent Urinary Tract Infections Caused by Multidrug Resistant Bacteria.

PURPOSE: Antimicrobial resistance leads to complications in the management of recurrent urinary tract infections. In some patients with recurrent urinary tract infections who have limited treatment options intravenous therapy with reserve antibiotics is often required. In this study we assessed the effectiveness, safety and feasibility of prophylactic treatment with intravesical gentamicin in patients with refractory recurrent urinary tract infections caused by multidrug resistant microorganisms. MATERIALS AND METHODS: This was a prospective trial of 63 adults with recurrent urinary tract infections caused by multidrug resistant pathogens who were enrolled at 1 academic and 1 general hospital in The Netherlands between 2014 and 2017. The intervention was overnight intravesical instillations of gentamicin for 6 months. The primary outcome was the recurrence rate of urinary tract infections compared to that in the preceding 6 months. Secondary objectives included assessment of the safety of intravesical gentamicin instillation and its influence on the development of antibiotic resistance in uropathogens. RESULTS: The mean number of urinary tract infections was reduced from 4.8 to 1.0 during intravesical treatment. The resistance rate of the uropathogens decreased from 78% to 23%. No systemic absorption or clinically relevant side effects were observed. CONCLUSIONS: Intravesical gentamicin instillation reduced the number of urinary tract infection episodes and the degree of antimicrobial resistance.

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.

Ecological effects of selective decontamination on resistant gram-negative bacterial colonization.

RATIONALE: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) eradicate gram-negative bacteria (GNB) from the intestinal and respiratory tract in intensive care unit (ICU) patients, but their effect on antibiotic resistance remains controversial. OBJECTIVES: We quantified the effects of SDD and SOD on bacterial ecology in 13 ICUs that participated in a study, in which SDD, SOD, or standard care was used during consecutive periods of 6 months (de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, et al. N Engl J Med 2009;360:20-31). METHODS: Point prevalence surveys of rectal and respiratory samples were performed once monthly in all ICU patients (receiving or not receiving SOD/SDD). Effects of SDD on rectal, and of SDD/SOD on respiratory tract, carriage of GNB were determined by comparing results from consecutive point prevalence surveys during intervention (6 mo for SDD and 12 mo for SDD/SOD) with consecutive point prevalence data in the pre- and postintervention periods. MEASUREMENTS AND MAIN RESULTS: During SDD, average proportions of patients with intestinal colonization with GNB resistant to either ceftazidime, tobramycin, or ciprofloxacin were 5, 7, and 7%, and increased to 15, 13, and 13% postintervention (P < 0.05). During SDD/SOD resistance levels in the respiratory tract were not more than 6% for all three antibiotics but increased gradually (for ceftazidime; P < 0.05 for trend) during intervention and to levels of 10% or more for all three antibiotics postintervention (P < 0.05). CONCLUSIONS: SOD and SDD have marked effects on the bacterial ecology in an ICU, with rising ceftazidime resistance prevalence rates in the respiratory tract during intervention and a considerable rebound effect of ceftazidime resistance in the intestinal tract after discontinuation of SDD.

Using local clinical and microbiological data to develop an institution specific carbapenem-sparing strategy in sepsis: a nested case-control study.

Background: From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negative pathogens with resistance to empiric sepsis therapy is increasing. How and when to escalate standard sepsis therapy to a reserve antimicrobial agent, is a recurrent dilemma. The study objective was to develop decision strategies for empiric sepsis therapy based on local microbiological and clinical data, and estimate the number needed to treat with a carbapenem to avoid mismatch of empiric therapy in one patient (NNTC). Methods: We performed a nested case control study in patients (> 18 years) with Gram-negative bacteremia in 2013-2016. Cases were defined as patients with Gram-negative bacteremia with in vitro resistance to the combination 2nd generation cephalosporin AND aminoglycoside (C-2GC + AG). Control patients had Gram-negative bacteremia with in vitro susceptibility to cefuroxime AND/OR gentamicin, 1:2 ratio. Univariate and multivariable analysis was performed for demographic and clinical predictors of resistance. The adequacy rates of empiric therapy and the NNTC were estimated for different strategies. Results: The cohort consisted of 486 episodes of Gram-negative bacteremia in 450 patients. Median age was 66 years (IQR 56-74). In vitro resistance to C-2GC + AG was present in 44 patients (8.8%). Independent predictors for resistance to empiric sepsis therapy were hematologic malignancy (adjusted OR 4.09, 95%CI 1.43-11.62, p < 0.01), previously cultured drug resistant pathogen (adjusted OR 3.72. 95%CI 1.72-8.03, p < 0.01) and antibiotic therapy during the preceding 2 months (adjusted OR 12.5 4.08-38.48, p < 0.01). With risk-based strategies, an adequacy rate of empiric therapy of 95.2-99.3% could be achieved. Compared to treating all patients with a carbapenem, the NNTC could be reduced by 82.8% (95%CI 78.5-87.5%) using the targeted approaches. Conclusions: A risk-based approach in empiric sepsis therapy has the potential to better target the use of reserve antimicrobial agents aimed at multi-resistant Gram-negative pathogens. A structured evaluation of the expected antimicrobial consumption and antibiotic adequacy rates is essential to be able to weigh the costs and benefits of potential antibiotic strategies and select the most appropriate approach.