Synergic combinations of antimicrobial peptides (AMPs) against biofilms of methicillin-resistant Staphylococcus aureus (MRSA) on polystyrene and medical devices.

Abstract Objectives Antimicrobial research is being focused to look for more effective therapeutics against antibiotic-resistant infections caused by methicillin-resistantStaphylococcus aureus (MRSA). In this direction, antimicrobial peptides (AMP) appears a promising solution. The aim of the present study was to investigate the potential activity of Temporin A, Citropin 1.1, CA(1–7)M(2–9)NH2 and Pal-KGK-NH2 in synergic activity against MRSA biofilms developed on polystyrene surface (PSS) and central venous catheter (CVC). Methods The research was subdivided into distinct phases to assess the ability of AMPs to inhibit biofilm formation, to identify a possible synergy between AMPs, and to eradicate preformed biofilms on PSS and CVC using AMPs alone or in combination. Results The activity of the AMPs was particularly evident in the inhibition of biofilm formation on PSS and on CVC, while the eradication of preformed biofilms was more difficult and was reached only after 24 h of contact. The synergic activity of AMPs combinations, selected by their FICI, has led to an improvement in the performance of all the molecules in the removal of different biofilms. Conclusions Overall, AMPs could represent the next generation of antimicrobial agents for a prophylactic or therapeutic tool to control biofilm of antibiotic-resistant and/or biofilm-associated infections on different medical devices

Role of Daptomycin in Cutaneous Wound Healing: A Narrative Review

Daptomycin is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and the on-label indications for its use include complicated skin and skin structure infections (cSSSI). We performed a narrative review of the literature with the aim to evaluate the role of daptomycin in the skin wound healing process, proposing our point of view on the possible association with other molecules that could improve the skin healing process. Daptomycin may improve wound healing in MRSA-infected burns, surgical wounds, and diabetic feet, but further studies in humans with histological examination are needed. In the future, the combination of daptomycin with other molecules with synergistic action, such as vitamin E and derivates, IB-367, RNA III-inhibiting peptide (RIP), and palladium nanoflowers, may help to improve wound healing and overcome forms of antibiotic resistanc

Clinical and microbiological features of ceftolozane/tazobactam-resistant Pseudomonas aeruginosa isolates in a university hospital in central Italy

Objectives: Ceftolozane/tazobactam (C/T) is a novel cephalosporin and β-lactamase inhibitor combination with great activity against Pseudomonas aeruginosa. To assess P. aeruginosa susceptibility to C/T, a surveil- lance study was conducted from October 2018 to March 2019 at the University Hospital ‘Ospedali Riuniti’ in Ancona, Italy. Methods: Minimum inhibitory concentrations (MICs) to C/T were determined by Etest strip. Resistant iso- lates were characterized by phenotypic (broth microdilution antimicrobial susceptibility testing and mod- ified Carbapenem Inactivation Method [mCIM]) and genotypic (Polymerase Chain Reaction [PCR], Pulsed Field Gel Electrophoresis [PFGE], and whole-genome sequencing [WGS]) methods. Clinical variables of patients infected by C/T-resistant P. aeruginosa were collected from medical records. Results: Fifteen of 317 P. aeruginosa collected showed resistance to C/T (4.7%). Ten strains demonstrated carbapenemase activity by mCIM method, and PCR confirmed that eight strains harbored a blaVIM gene while the other two were positive for blaIMP. Additionally, three isolates carried acquired extended spec- trum β-lactamase genes (two isolates carried blaPER and one carried blaGES). Eight strains were strictly related by PFGE and WGS analysis confirmed that they belonged to sequence type (ST)111. The other STs found were ST175 (two isolates), ST235 (two isolates), ST70 (one isolate), ST621 (one isolate), and the new ST3354 (one isolate). Most patients had received previous antibiotic therapies, carried invasive devices, and experienced prolonged hospitalization. Conclusion: This study demonstrated the presence of C/T-resistant P. aeruginosa isolates in a regional hospital carrying a number of resistance mechanisms acquired by different high-risk clone

Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)

The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice

Economic consequences of investing in anti-HCV antiviral treatment from the Italian NHS perspective : a real-world-based analysis of PITER data

OBJECTIVE: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. METHODS: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. RESULTS: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. CONCLUSIONS: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV

Valutazione del grado di fibrosi cistica mediante metodica elastometrica in pazienti monoinfetti e coinfetti da HIV e HCV

Introduzione Con l’aumentata efficacia della terapia antiretrovirale di combinazione (cART), il numero di persone che sopravvivono con HIV è in incremento. L’epatite cronica HCV correlata rappresenta una delle principali cause di mortalità e morbidità non-AIDS correlata nei pazienti HIV positivi. Metodi Abbiamo confrontato la fibrosi epatica rilevata tramite metodica elastometrica (Fibroscan) in tre popolazioni di pazienti seguiti presso la Clinica di Malattie Infettive dell’Università di Ancona dall’ottobre 2009 al novembre 2012: monoinfetti HCV (HCV), coinfetti HIV-HCV (HIV/HCV) e monoinfetti HIV (HIV). Risultati Sono stati arruolati un totale di 354 soggetti: 98 HIV, 70 HIV-HCV e 186 HCV. Sono stati esclusi i pazienti con epatite B e cirrosi epatica scompensata. I pazienti HIV/HCV presentavano una più lunga durata delle infezioni da HIV (P=0.006) e HCV (P=0.001). Inoltre, assumevano cART da più tempo (P=0.001), avevano maggiore prevalenza di lipodistrofia (P=0.001) e più alta carica virale HCV (P=0.004). La fibrosi epatica è significativamente maggiore negli HCV e HIV/HCV rispetto ai pazienti HIV (P<0.001); non si sono osservate differenze tra HCV e HIV/HCV. La fibrosi epatica di grado moderato/severo è significativamente associata alla didanosina (ddi), abacavir (ABC), stavudina (d4T) e lopinavir (LPV/r) (P comprese tra <0.001 e 0.004). I risultati della regressione logistica mostrano che la coinfezione (P<0.001), l’età (P<0.001) e le AST (P=0.007) sono associate in maniera statisticamente significativa a sviluppo di fibrosi epatica di grado moderato/severo. Conclusioni Nel nostro studio la coinfezione HIV-HCV, l’età e il valore delle AST sono associate a un incremento della fibrosi epatica nei soggetti HIV positivi

Antifungal Combinations in Dermatophytes

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations against dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies and 31 articles referring to case reports or clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts or essential oils, calcineurin inhibitors, peptides, disinfectant agents, and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections, an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e., terbinafine, griseofulvin, or azole—mainly itraconazole) plus a topical medication (i.e., azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful to accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available so far, it is desirable to continue the research in this field

The Clinical Characteristics of Bloodstream Infections Due to <i>Candida</i> spp. in Patients Hospitalized in Intensive Care Units during the SARS-CoV-2 Pandemic: The Results of a Multicenter Study

Candidemia is a serious health threat. Whether this infection has a greater incidence and a higher mortality rate in patients with COVID-19 is still debated. In this multicenter, retrospective, observational study, we aimed to identify the clinical characteristics associated with the 30-day mortality in critically ill patients with candidemia and to define the differences in candidemic patients with and without COVID-19. Over a three-year period (2019–2021), we identified 53 critically ill patients with candidemia, 18 of whom (34%) had COVID-19 and were hospitalized in four ICUs. The most frequent comorbidities were cardiovascular (42%), neurological (17%), chronic pulmonary diseases, chronic kidney failure, and solid tumors (13% each). A significantly higher proportion of COVID-19 patients had pneumonia, ARDS, septic shock, and were undergoing an ECMO procedure. On the contrary, non-COVID-19 patients had undergone previous surgeries and had used TPN more frequently. The mortality rate in the overall population was 43%: 39% and 46% in the COVID-19 and non-COVID-19 patients, respectively. The independent risk factors associated with a higher mortality were CVVH (HR 29.08 [CI 95% 3.37–250]) and a Charlson’s score of > 3 (HR 9.346 [CI 95% 1.054–82.861]). In conclusion, we demonstrated that candidemia still has a high mortality rate in patients admitted to ICUs, irrespective of infection due to SARS-CoV-2

Antifungal Combinations against Candida Species: From Bench to Bedside

Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal armamentarium, the rising of drug-resistance and the persistence of a high mortality rate in systemic candidiasis have led to an increased interest in combination therapy. Therefore, we aimed to review the scientific literature concerning the antifungal combinations against Candida. A literature search performed in PubMed yielded 92 studies published from 2000 to 2021: 29 articles referring to in vitro studies, six articles referring to either in vitro and in vivo (i.e., animal models) studies and 57 clinical articles. Pre-clinical studies involved 735 isolates of Candida species and 12 unique types of antifungal combination approaches including azoles plus echinocandins (19%), polyenes plus echinocandins (16%), polyenes plus azoles (13%), polyenes plus 5-flucytosine ([5-FC], 13%), azoles plus 5-FC (11%) and other types of combinations (28%). Results varied greatly, often being species-, drug- and methodology-dependent. Some combinatorial regimens exerted a synergistic effect against difficult-to-treat Candida species (i.e., azoles plus echinocandins; polyenes plus 5-FC) or they were more effective than monotherapy in prevent or reducing biofilm formation and in speeding the clearance of infected tissues (i.e., polyenes plus echinocandins). In 283 patients with documented Candida infections (&gt;90% systemic candidiasis/BSI), an antifungal combination approach could be evaluated. Combinations included: azoles plus echinocandins (36%), 5-FC-combination therapies (24%), polyenes plus azoles (18%), polyenes plus echinocandins (16%) and other types of combination therapy (6%). Case reports describing combination therapies yielded favorable response in most cases, including difficult-to-treat fungal infections (i.e., endocarditis, osteoarticular infections, CNS infections) or difficult-to-treat fungal pathogens. The only randomized trial comparing amphotericin-B deoxycholate (AMB) plus FLU vs. AMB alone for treatment of BSI in nonneutropenic patients showed that the combination trended toward improved success and more-rapid clearance from the bloodstream. In summary, antifungal combinations against Candida have produced great interest in the past two decades. To establish whether this approach can become a reliable treatment option, additional in vitro and clinical data are warranted

Candidemia: Evolution of Drug Resistance and Novel Therapeutic Approaches

none5Candidemia and invasive candidiasis are the most common healthcare-associated invasive fungal infections, with a crude mortality rate of 25-50%. Candida albicans remains the most frequent etiology, followed by C. glabrata, C. parapsilosis and C. tropicalis. With the exception of a limited number of species (ie: C. krusei, C. glabrata and rare Candida species), resistance to fluconazole and other triazoles are quite uncommon. However, recently fluconazoleresistant C. parapsilosis, echinocandin-resistant C. glabrata and the multidrug resistant C. auris have emerged. Resistance to amphotericin B is even more rare due to the reduced fitness of resistant isolates. The mechanisms of antifungal resistance in Candida (altered drug-target interactions, reduced cellular drug concentrations, and physical barriers associated with biofilms) are analyzed. The choice of the antifungal therapy for candidemia must take into account several factors such as type of patient, presence of devices, severity of illness, recent exposure to antifungals, local epidemiology, organs involvement, and Candida species. The first-line therapy in nonneutropenic critical patient is an echinocandin switching to fluconazole in clinically stable patients with negative blood cultures and azole susceptible isolate. Similarly, an echinocandin is the drug of choice also in neutropenic patients. The treatment duration is 14 days after the first negative blood culture or longer in cases of organ involvement. An early removal of vascular catheter improves the outcome. The promising results of new antifungal molecules, such as the terpenoid derivative ibrexafungerp, the novel echinocandin with an enhanced half-life rezafungin, oteseconazole and fosmanogepix, representative of new classes of antifungals, are discussed.mixedTortorano, Anna Maria; Prigitano, Anna; Morroni, Gianluca; Brescini, Lucia; Barchiesi, FrancescoTortorano, Anna Maria; Prigitano, Anna; Morroni, Gianluca; Brescini, Lucia; Barchiesi, Francesc