Subject(s)
Aztreonam , Klebsiella Infections , Humans , Meropenem/therapeutic use , Aztreonam/pharmacology , Aztreonam/therapeutic use , Klebsiella pneumoniae , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , beta-Lactamases , Drug Combinations , Microbial Sensitivity Tests , Klebsiella Infections/drug therapyABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects , COVID-19 Drug TreatmentABSTRACT
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.
Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents/therapeutic use , Carbapenems , Cephalosporins , Humans , Intensive Care Units , Microbial Sensitivity Tests , Prospective Studies , beta-Lactamases , CefiderocolABSTRACT
OBJECTIVE: To evaluate the feasibility of "in-office" TPFBx under local anesthesia (LA). MATERIALS AND METHODS: We prospectively screened for eligibility data of 724 consecutive men undergoing either TPFBx (target and systematic cores) or TPSBx (systematic cores only) from September 2016 to June 2018 due to suspicion of prostate cancer (CaP), according to predefined exclusion criteria. RESULTS: We included 459 men (TPFBx nâ¯=â¯279 including nâ¯=â¯338 mpMRI lesions, Pi-RADS 4 in 63.6%; TPSBx nâ¯=â¯180). Median procedural time and maximum pain were 19 minutes and 5 numeric rating scale (NRS) points; pain was highest at the time of LA. Only 1 major complication occurred (Clavien 3a). Hematuria and hematospermia were frequent (72.6% and 54.2%). Vaso-vagal reactions and AUR were rare (0.7% and 0.4%). No cases of UTI and 1 case of fever were recorded. No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx (Pâ¯=â¯.86 and Pâ¯=â¯.89). In comparison with TPSBx the sole differences were pain during prostatic sampling (Pâ¯=â¯.03), duration of hematospermia (P <.0001) and procedural time (P <.001) all higher for TPFBx. Clinically significant (cs) CaP was detected in nâ¯=â¯150 (53.8%) patients in the TPFBx group (34.9%, 51.7%, and 75% of Pirads 3, 4, and 5, respectively). Addition of systematic cores detected nâ¯=â¯25 csCaP that were missed by targeted cores (17.4% of all csCaP). CONCLUSION: TPFBx under LA are feasible, yielding high tolerability, low complications, no impact on erectile and urinary function and good csCaP detection. Addition of systematic to targeted cores remains recommended. Further studies are needed to confirm our findings.
Subject(s)
Hematuria , Hemospermia , Image-Guided Biopsy , Multiparametric Magnetic Resonance Imaging/methods , Postoperative Complications , Prostate , Prostatic Neoplasms/pathology , Ultrasonography, Interventional/methods , Aged , Ambulatory Surgical Procedures/adverse effects , Ambulatory Surgical Procedures/methods , Ambulatory Surgical Procedures/statistics & numerical data , Anesthesia, Local/methods , Feasibility Studies , Hematuria/diagnosis , Hematuria/etiology , Hemospermia/diagnosis , Hemospermia/etiology , Humans , Image-Guided Biopsy/adverse effects , Image-Guided Biopsy/methods , Image-Guided Biopsy/statistics & numerical data , Italy/epidemiology , Male , Multimodal Imaging/methods , Pain, Procedural/prevention & control , Penile Erection , Postoperative Complications/diagnosis , Postoperative Complications/physiopathology , Postoperative Complications/prevention & control , Prostate/diagnostic imaging , Prostate/pathology , Prostatic Neoplasms/epidemiology , UrinationABSTRACT
Ceftazidime/avibactam (CAZ-AVI) is a novel, fixed-dose combination antibiotic that has been approved in Europe and the United States for patients with complicated urinary tract infections (cUTIs) based on results of a Phase III, randomized, comparative study (RECAPTURE study). The present analysis evaluated cost-effectiveness of CAZ-AVI as an empirical treatment for hospitalized patients with cUTIs from the Italian publicly funded healthcare (third-party payer) perspective. A sequential, patient-level simulation model was developed that followed the clinical course of cUTI and generated 5000 pairs of identical patients (CAZ-AVI or imipenem as empirical treatment). The model included additional impact of resistant pathogens; patients who did not respond to empirical treatment were switched to second-line treatment of colistin+high dose carbapenem in both groups. The time horizon of the model was five years, with an annual discount rate of 3% applied to both costs and quality-adjusted life-years (QALYs). The analysis demonstrated that an intervention sequence (CAZ-AVI followed by colistin+high dose carbapenem) compared with a comparator sequence (imipenem followed by colistin+high dose carbapenem) was associated with a net incremental cost of 1015 per patient but provided better health outcomes in terms of clinical cure (97.65% vs. 91.08%; ∆â¯=â¯6.57%), shorter hospital stays (10.65 vs. 12.55 days; ∆â¯=â¯1.90 days), and QALYs gained per patient (4.190 vs. 4.063; ∆â¯=â¯0.126). The incremental cost-effectiveness ratio was 8039/QALY, which is well below the willingness-to-pay threshold of 30 000/QALY in Italy. The results showed that CAZ-AVI is expected to be a cost-effective treatment compared with imipenem for cUTI in Italy.
Subject(s)
Anti-Bacterial Agents/economics , Azabicyclo Compounds/economics , Ceftazidime/economics , Cost-Benefit Analysis/methods , Imipenem/economics , Length of Stay/economics , Urinary Tract Infections/drug therapy , Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/therapeutic use , Carbapenems/economics , Carbapenems/therapeutic use , Ceftazidime/therapeutic use , Colistin/economics , Colistin/therapeutic use , Drug Combinations , Europe , Gram-Negative Bacteria/drug effects , Humans , Imipenem/therapeutic use , National Health Programs , United States , Urinary Tract Infections/microbiologyABSTRACT
We present the case of a patient with ventilator-associated pneumonia (VAP) caused by a pan-resistant Acinetobacter baumannii successfully treated with the combination colistin plus vancomycin plus rifampin, whose in vitro activity was investigated by checkerboard method and killing testing. Furthermore, the serum bactericidal activity (SBA) was assessed. Our case shows that an innovative regimen consisting of colistin plus antimicrobials active only against Gram-positive microorganisms might represent a valid therapeutic option for severe infections caused by colistin-resistant A. baumannii.
Subject(s)
Acinetobacter Infections/microbiology , Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/therapeutic use , Colistin/pharmacology , Pneumonia, Ventilator-Associated/microbiology , Acinetobacter Infections/drug therapy , Aged , Anti-Bacterial Agents/pharmacology , Antibiotics, Antitubercular/pharmacology , Antibiotics, Antitubercular/therapeutic use , Colistin/therapeutic use , Drug Resistance, Multiple, Bacterial , Drug Therapy, Combination , Humans , Male , Microbial Sensitivity Tests , Neurosurgical Procedures , Pneumonia, Ventilator-Associated/drug therapy , Rifampin/pharmacology , Rifampin/therapeutic use , Subarachnoid Hemorrhage/surgery , Vancomycin/pharmacology , Vancomycin/therapeutic useABSTRACT
During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel ß-lactamase inhibitor with activity against various ß-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C ß-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Thus, combination with this inhibitor expands ceftazidime's spectrum of activity to MDR Enterobacteriaceae and Pseudomonas aeruginosa strains. In Phase II clinical trials of patients with complicated intra-abdominal infections and complicated urinary tract infections ceftazidime/avibactam exhibited clinical efficacy comparable to those of meropenem and imipenem/cilastatin, respectively. A Phase III clinical trial confirmed the efficacy of ceftazidime/avibactam in patients with MDR Enterobacteriaceae and P. aeruginosa infections. Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are also discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/therapeutic use , Ceftazidime/therapeutic use , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Animals , Anti-Bacterial Agents/administration & dosage , Azabicyclo Compounds/administration & dosage , Bacterial Proteins/antagonists & inhibitors , Ceftazidime/administration & dosage , Clinical Trials as Topic , Drug Therapy, Combination , Gram-Negative Bacterial Infections/microbiology , Humans , Intraabdominal Infections/drug therapy , Klebsiella pneumoniae/drug effects , Mice , Microbial Sensitivity Tests , Urinary Tract Infections/drug therapy , beta-Lactamase Inhibitors/therapeutic use , beta-Lactamases/metabolismABSTRACT
Gram-positive cocci are a well-recognised major cause of nosocomial infection worldwide. Bloodstream infections due to methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, and multi-drug resistant enterococci are a cause of concern for physicians due to their related morbidity and mortality rates. Aim of this article is to review the current state of knowledge regarding the management of BSI caused by staphylococci and enterococci, including infective endocarditis, and to identify those factors that may help physicians to manage these infections appropriately. Moreover, we discuss the importance of an appropriate use of antimicrobial drugs, taking in consideration the in vitro activity, clinical efficacy data, pharmacokinetic/pharmacodynamic parameters, and potential side effects.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Endocarditis, Bacterial/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Staphylococcal Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Bacteremia/microbiology , Coagulase/metabolism , Endocarditis, Bacterial/microbiology , Enterococcus faecalis , Gram-Positive Bacterial Infections/complications , Humans , Methicillin-Resistant Staphylococcus aureus/enzymology , Microbial Sensitivity Tests , Staphylococcal Infections/complications , Vancomycin-Resistant EnterococciABSTRACT
Post-neurosurgical infection is a serious complication that occurs in approx. 4% of all patients undergoing neurosurgical procedures and is associated with high morbidity and mortality rates and prolonged length of intensive care unit (ICU) stay. Coagulase-negative staphylococci (CoNS), especially methicillin-resistant Staphylococcus epidermidis (MRSE), are the most frequent pathogens involved in CNS post-neurosurgical meningitis. Treatment is challenging especially in patients with meningitis due to multidrug- resistant (MDR) CONS. Herein, we report a unique case of post-neurosurgical meningitis due to MRSE resistant to linezolid (a molecular analysis revealed the presence of the mutation G2576T on domain V of the 23S rRNA gene) and with reduced susceptibility to glycopeptides, successfully treated with a combination of daptomycin at 10 mg/kg daily plus trimethoprim/sulfamethoxazole (TMP/SMX). This antibiotic combination showed an indifferent interaction in in vitro studies. Daptomycin serum and cerebrospinal fluid (CSF) concentrations, determined through blood and CSF samples drawn just prior to and 4 h after the third dose, were 18.9-0.78 and 51.65-3.1 mg/L, respectively. These values allowed us to approximate a 5-6% penetration rate of the drug through an inflamed blood-brain barrier. In conclusion, although further studies are needed, combination of high-dose daptomycin plus TMP/SMX is a reasonable option for treatment of meningitis caused by multidrug-resistant S. epidermidis.
Subject(s)
Acetamides/therapeutic use , Daptomycin/therapeutic use , Meningitis/drug therapy , Oxazolidinones/therapeutic use , Prosthesis-Related Infections/microbiology , Staphylococcus epidermidis/drug effects , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Anti-Bacterial Agents/therapeutic use , Blood-Brain Barrier/drug effects , Daptomycin/blood , Daptomycin/cerebrospinal fluid , Female , Glycopeptides/therapeutic use , Humans , Linezolid , Meningitis/surgery , Methicillin Resistance/drug effects , Microbial Sensitivity Tests , Middle Aged , Staphylococcus epidermidis/isolation & purification , Treatment Outcome , Trimethoprim, Sulfamethoxazole Drug Combination/blood , Trimethoprim, Sulfamethoxazole Drug Combination/cerebrospinal fluidABSTRACT
The aim of this study was to ascertain the incidence and clinical significance of metallo-beta-lactamases among Enterobacter strains isolated from patients with nosocomial infections. We prospectively collected data on patients with Enterobacter infection during a 13-month period. All of the strains were investigated for antibiotic susceptibility, the presence and expression of metallo-beta-lactamases, and clonality. Of 29 infections (11 involving the urinary tract, 7 pneumonias, 3 skin/soft tissue infections, 3 intra-abdominal infections, 3 bacteremias, and 2 other infections), 7 (24%) were caused by Enterobacter cloacae strains harboring a bla(VIM-1) gene associated or not with a bla(SHV12) gene. Infections caused by VIM-1-producing strains were more frequently associated with a recent prior hospitalization (P = 0.006), cirrhosis (P = 0.03), relapse of infection (P < 0.001), and more prolonged duration of antibiotic therapy (P = 0.01) than were other infections. All of the isolates were susceptible to imipenem and meropenem and had bla(VIM-1) preceded by a weak P1 promoter and inactivated P2 promoters. Most VIM-1-producing Enterobacter isolates belonged to a main clone, but four different clones were found. Multiclonal VIM-1-producing E. cloacae infections are difficult to diagnose due to an apparent susceptibility to various beta-lactams, including carbapenems, and are associated with a high relapse rate and a more prolonged duration of antibiotic therapy.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cross Infection/drug therapy , Cross Infection/microbiology , Enterobacter cloacae/enzymology , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/microbiology , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Bacterial Typing Techniques , DNA Fingerprinting , Drug Resistance, Bacterial , Enterobacter cloacae/classification , Enterobacter cloacae/genetics , Enterobacter cloacae/isolation & purification , Female , Genotype , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Treatment Outcome , Young Adult , beta-Lactamases/biosynthesisABSTRACT
Fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method, we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL, that is easily achievable in serum at standard dosing regimens, against seven methicillin-resistant Staphylococcus aureus strains, isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy. MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. Fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.