Cefiderocol as Rescue Therapy for Acinetobacter baumannii and Other Carbapenem-resistant Gram-negative Infections in Intensive Care Unit Patients.

Ten critically ill patients with either bacteremia or ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii, Stenotrophomonas maltophilia, or New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae received cefiderocol. All strains had minimum inhibitory concentration ≤2 µg/mL. Thirty-day clinical success and survival rates were 70% and 90%, respectively. Two patients had a microbiological failure. Future prospective studies are warranted.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections.

OBJECTIVES: The aim of this study was to investigate the diagnostic performance of (99m)Tc-hexamethypropylene amine oxime labeled autologous white blood cell ((99m)Tc-HMPAO-WBC) scintigraphy in patients with suspected infections associated with cardiovascular implantable electronic devices (CIEDs). BACKGROUND: Early, definite recognition of CIED-related infections combined with accurate localization and quantification of disease burden is a prerequisite for optimal treatment strategies. METHODS: All 63 consecutive patients underwent clinical examination, blood chemistry, microbiology, and echography of the cardiac region/venous pathway of the device. Final diagnosis of infection was established in 32 of 63 patients and in 23 of 32 by microbiology. RESULTS: Sensitivity of (99m)Tc-HMPAO-WBC single-photon emission computed tomography/computed tomography (SPECT/CT) was 94% for both detection and localization of CIED-associated infection. SPECT/CT imaging had a definite added diagnostic value over both planar and stand-alone SPECT. Pocket infection was often associated with lead(s) involvement; the intracardiac portion of the lead(s) more frequently exhibited (99m)Tc-HMPAO-WBC accumulation and presented the highest rate of complications, infectious endocarditis, and septic embolism. Two false negative cases and no false positive results were observed. None of the patients with negative (99m)Tc-HMPAO-WBC scintigraphy developed CIED-related infection during follow-up of 12 months. Echography of the cardiac region/venous pathway of the device had 90% specificity, but low sensitivity (81% when intracardiac lead[s] infection only was considered). The Duke criteria had 31% sensitivity for the definite category (100% specificity) and 81% for the definite and possible categories (77% specificity). CONCLUSIONS: (99m)Tc-HMPAO-WBC scintigraphy enabled the confirmation of the presence of CIED-associated infection, definition of the extent of device involvement, and detection of associated complications. Moreover, (99m)Tc-HMPAO-WBC scintigraphy reliably excluded device-associated infection during a febrile episode and sepsis, with 95% negative predictive value.

Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections.

A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4-12 mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution (V(d)) of 0.19 ± 0.05 L/kg. Creatinine clearance (CL(Cr)) was identified as having a significant influence on daptomycin CL, and a decrease in CL(Cr) of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased Vd. MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol.

Micafungin for Candida albicans pacemaker-associated endocarditis: a case report and review of the literature.

We report on the treatment with micafungin of a pacemaker-associated endocarditis due to Candida albicans. Antifungal therapy was able to reduce vegetation size from 5 to 1 cm making possible the transvenous removal of the device without a high risk of pulmonary embolism. Noteworthy, a high micafungin concentration was documented into the lead vegetation (10 µg/g of vegetation tissue) and this may have contributed to the striking size reduction of vegetation.

[New options for treatment of intraabdominal infections: tigecycline]. / Nuove opzioni terapeutiche per le infezioni intraddominali: la tigeciclina.

Tigecycline is a new antimicrobial agent; it is the first in a new class of antibiotics, the glycylcyclines, with properties conferring the ability to overcome many common resistance mechanisms, thus allowing its use for many serious and life-threatening infections for which the use of other antibiotics is no longer appropriate. It has a wide antibacterial spectrum including most methicillin-resistant Staphylococci, vancomycin-resistant Enterococci, ESBL-producing Gram negative bacteria, and other MDR Gram negative bacteria such as Acinetobacter, and Stenotrophomonas. It has good antibacterial activity also against anaerobes and atypical pathogens. Tigecycline is available only as parenteral formulation. It has a high volume of distribution (>10 l/kg), and long half-life (36 hrs). It has been approved in USA and Europe for the treatment of complicated skin and soft tissue infections and for the complicated community acquired intra-abdominal infections. Phase III studies for treatment of community acquired and nosocomial acquire pneumonia, and sepsis sustained by multi-drug-resistant pathogens are ongoing.