Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin.

INTRODUCTION: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. AREAS COVERED: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. EXPERT OPINION: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

Interplay between Klebsiella pneumoniae producing KPC-31 and KPC-3 under treatment with high dosage meropenem: a case report.

The objective was to study ceftazidime-avibactam resistant and susceptible Klebsiella pneumoniae isolated from a patient admitted to the Policlinico Umberto I of Rome for SARS-CoV2. Data on the evolution of patient's conditions, antimicrobial therapies, and microbiological data were collected. Whole-genome sequencing performed by Illumina and Nanopore sequencing methods were used to type the strains. During the hospitalization, a SARS-CoV2-infected patient was colonized by a KPC-producing K. pneumoniae strain and empirically treated with ceftazidime-avibactam (CZA) when presenting spiking fever symptoms. Successively, ST2502 CZA-resistant strain producing the KPC-31 variant gave a pulmonary infection to the patient. The infection was treated with high doses of meropenem. The KPC-31-producing strain disappeared but the patient remained colonized by a KPC-3-producing K. pneumoniae strain. An interplay between highly conserved KPC-31- and KPC-3-producing ST2502 strains occurred in the SARS-CoV2 patient during the hospitalization, selected by CZA and carbapenem treatments, respectively.

Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumonia.

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.

Evidence-based criteria for the choice and the clinical use of the most appropriate lock solutions for central venous catheters (excluding dialysis catheters): a GAVeCeLT consensus.

BACKGROUND: The most appropriate lock solution for central venous access devices is still to be defined. GAVeCeLT - the Italian group for venous access devices - has developed a consensus on the evidence-based criteria for the choice and the clinical use of the most appropriate lock solution for central venous catheters (excluding dialysis catheters). METHOD: After the constitution of a panel of experts, a systematic collection and review of the literature has been performed, focusing on clinical studies dealing with lock solutions used for prevention of occlusion (heparin, citrate, urokinase, recombinant tissue plasminogen activator [r-TPA], normal saline) or for prevention of infection (citrate, ethanol, taurolidine, ethylene-diamine-tetra-acetic acid [EDTA], vancomycin, linezolid and other antibiotics), in both adults and in pediatric patients. Studies on central lines used for dialysis or pheresis, on peripheral venous lines and on arterial lines were excluded from this analysis. Studies on lock solutions used for treatment of obstruction or infection were not considered. The consensus has been carried out according to the Delphi method. RESULTS: The panel has concluded that: (a) there is no evidence supporting the heparin lock; (b) the prevention of occlusion is based on the proper flushing and locking technique with normal saline; (c) the most appropriate lock solution for infection prevention should include citrate and/or taurolidine, which have both anti-bacterial and anti-biofilm activity, with negligible undesired effects if compared to antibiotics; (d) the patient populations most likely to benefit from citrate/taurolidine lock are yet to be defined. CONCLUSIONS: The actual value of heparinization for non-dialysis catheters should be reconsidered. Also, the use of lock with substances with anti-bacterial and anti-biofilm activity (such as citrate or taurolidine) should be taken into consideration in selected populations of patients.

The role of vancomycin in addition with colistin and meropenem against colistin-sensitive multidrug resistant Acinetobacter baumannii causing severe infections in a Paediatric Intensive Care Unit.

BACKGROUND: Acinetobacter baumannii has been associated with high morbidity and mortality rates, even in pediatric patients. Therapeutic options are limited, especially when the strain is multidrug resistant. METHODS: Clinical and microbiological analyses of 4 cases of systemic infections caused by multi drug resistant A. baumannii treated with colistin/vancomycin combination at a Pediatric Intensive Care Unit were performed in order to explore the potential synergistic activity of colistin plus vancomycin. All the patients were treated with colistin, meropenem and vancomycin. RESULTS: Four severe infections due to MDR A. baumannii were observed. All patients treated with colistin/vancomycin combination had a positive outcome with no infection relapses. Most importantly, no significant adverse events related to the simultaneous administration of COL plus VAN were observed. In our in-vitro experiments, the synergistic effect of the combination COL plus VAN showed an early bactericidal activity even at VAN concentration of 16 mg/L, which reflects the serum trough concentrations obtained in patients. DISCUSSION: An antimicrobial strategy based on the activity of colistin plus vancomycin was in-vitro and in-vivo effective in life-threatening infections caused by multidrug-resistant A. baumannii in a Pediatric Intensive Care Unit, in the absence of adverse effects. Colistin plus vancomycin were highly synergic and bactericidal against carbapenem-resistant, colistin sensitive A. baumannii whereas the addition of meropenem did not enhance the in-vitro activity of colistin plus vancomycin. CONCLUSIONS: Our results confirm existing data on the potential synergistic activity of a therapeutic strategy including colistin plus vancomycin and provide important new clinical information for its potential use as a therapeutic option against MDR A. baumannii infections, especially in the pediatric population.

Optimizing antibiotic therapy of bacteremia and endocarditis due to staphylococci and enterococci: new insights and evidence from the literature.

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.

Daptomycin plus trimethoprim/sulfamethoxazole combination therapy in post-neurosurgical meningitis caused by linezolid-resistant Staphylococcus epidermidis.

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.

Infections with VIM-1 metallo-{beta}-lactamase-producing enterobacter cloacae and their correlation with clinical outcome.

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.

In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy.

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.